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Review

Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020–2023)

, , &
Pages 141-158 | Received 18 Sep 2023, Accepted 27 Mar 2024, Published online: 09 Apr 2024

References

  • Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, et al. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010;11(5):329–341. doi: 10.1038/nrm2882
  • Vanhaesebroeck B, Stephens L, Hawkins P. PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol. 2012;13(3):195–203. doi: 10.1038/nrm3290
  • Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28(6):1075–1083. doi: 10.1200/JCO.2009.25.3641
  • Sanchez VE, Nichols C, Kim HN, et al. Targeting PI3K signaling in acute lymphoblastic leukemia. Int J Mol Sci. 2019;20(2):412. doi: 10.3390/ijms20020412
  • Ward S, Sotsios Y, Dowden J, et al. Therapeutic potential of phosphoinositide 3-kinase inhibitors. Chem Biol. 2003;10(3):207–213. doi: 10.1016/s1074-5521(03)00048-6
  • Mishra R, Patel H, Alanazi S, et al. PI3K inhibitors in cancer: Clinical implications and adverse effects. Int J Mol Sci. 2021;22(7):3464. doi: 10.3390/ijms22073464
  • Sabbah DA, Brattain MG, Zhong HA. Dual inhibitors of PI3K/mTOR or mTOR-selective inhibitors: which way shall we go? Curr Med Chem. 2011;18(36):5528–5544. doi: 10.2174/092986711798347298
  • Sabbah DA, Hu J, Zhong HA. Advances in the development of class i phosphoinositide 3-kinase (PI3K). CurrTop Med Chem. 2016;16(3):1413–1426. doi: 10.2174/1568026615666150915115823
  • Sabbah DA, Hajjo R, Bardaweel SK, et al. Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016-2020). Expert Opin Ther Pat. 2021;31(10):877–892.
  • Knight ZA, Gonzalez B, Feldman ME, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006;125(4):733–747.
  • Jia S, Roberts TM, Zhao JJ. Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol. 2009;21(2):199–208. doi: 10.1016/j.ceb.2008.12.007
  • Long HZ, Cheng Y, Zhou ZW, et al. PI3K/AKT signal pathway: A target of natural products in the prevention and treatment of Alzheimer’s disease and Parkinson’s disease. Front Pharmacol. 2021;12:648636. doi: 10.3389/fphar.2021.648636
  • Xie Y, Shi X, Sheng K, et al. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review). Mol Med Rep. 2019;19(2):783–791.
  • Shorning BY, Dass MS, Smalley MJ, et al. The PI3K-AKT-mTOR pathway and prostate cancer: at the crossroads of AR, MAPK, and WNT signaling. Int J Mol Sci. 2020;21(12):4507. doi: 10.3390/ijms21124507
  • Stefani C, Miricescu D, Stanescu S II, et al. Growth factors, PI3K/AKT/mTOR and MAPK signaling pathways in colorectal cancer pathogenesis: where are we now? Int J Mol Sci. 2021;22(19):10260.
  • Sun K, Luo J, Guo J, et al. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthr Cartil. 2020;28(4):400–409. doi: 10.1016/j.joca.2020.02.027
  • Barra F, Evangelisti G, Ferro Desideri L, et al. Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer. Expert Opin Investig Drugs. 2019;28(2):131–142. doi: 10.1080/13543784.2018.1558202
  • Stallone G, Infante B, Prisciandaro C, et al. mTOR and aging: an old fashioned dress. Int J Mol Sci. 2019;20(11):2774. doi: 10.3390/ijms20112774
  • Peng Y, Wang Y, Zhou C, et al. PI3K/Akt/mTOR pathway and its role in cancer therapeutics: Are we making headway? Front Oncol. 2022;12:819128. doi: 10.3389/fonc.2022.819128
  • Akbarzadeh M, Mihanfar A, Akbarzadeh S, et al. Crosstalk between miRNA and PI3K/AKT/mTOR signaling pathway in cancer. Life Sci. 2021;285:119984. doi: 10.1016/j.lfs.2021.119984
  • Fruman DA, Chiu H, Hopkins BD, et al. The PI3K pathway in human disease. Cell. 2017;170(4):605–635. doi: 10.1016/j.cell.2017.07.029
  • Faes S, Dormond O. PI3K and AKT: unfaithful partners in cancer. Int J Mol Sci. 2015;16(9):21138–21152. doi: 10.3390/ijms160921138
  • Trautmann M, Cyra M, Isfort I, et al. Phosphatidylinositol-3-kinase (PI3K)/Akt signaling is functionally essential in myxoid liposarcoma. Mol Cancer Ther. 2019;18(4):834–844. doi: 10.1158/1535-7163.MCT-18-0763
  • Shi X, Wang J, Lei Y, et al. Research progress on the PI3K/AKT signaling pathway in gynecological cancer (review). Mol Med Rep. 2019;19(6):4529–4535. doi: 10.3892/mmr.2019.10121
  • Chen H, Gao J, Du Z, et al. Expression of factors and key components associated with the PI3K signaling pathway in colon cancer. Oncol Lett. 2018;15(4):5465–5472. doi: 10.3892/ol.2018.8044
  • Vidal S, Bouzaher YH, El Motiam A, et al. Overview of the regulation of the class IA PI3K/AKT pathway by SUMO. Semin Cell Dev Biol. 2022;132:51–61. doi: 10.1016/j.semcdb.2021.10.012
  • He Y, Sun MM, Zhang GG, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. 2021;6(1):425. doi: 10.1038/s41392-021-00828-5
  • Zhou Y, Li S, Li J, et al. Effect of microRNA-135a on cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the IGF-1/PI3K/Akt signaling pathway in non-small cell lung cancer. Cell Physiol Biochem. 2017;42(4):1431–1446. doi: 10.1159/000479207
  • Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018;15(5):273–291. doi: 10.1038/nrclinonc.2018.28
  • Xue C, Li G, Lu J, et al. Crosstalk between circRnas and the PI3K/AKT signaling pathway in cancer progression. Signal Transduct Target Ther. 2021 Nov 24;6(1):400. doi: 10.1038/s41392-021-00788-w
  • Shayesteh L, Lu Y, Kuo WL, et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet. 1999;21(1):99–102. doi: 10.1038/5042
  • Samuels Y, Diaz LA, Schmidt-Kittler O, et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell. 2005;7(6):561–573. doi: 10.1016/j.ccr.2005.05.014
  • Samuels Y, Velculescu VE. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle. 2004;3(10):1221–1224. doi: 10.4161/cc.3.10.1164
  • Samuels Y, Wang ZH, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304(5670):554. doi: 10.1126/science.1096502
  • Zhang M, Jang H, Nussinov R. PI3K driver mutations: a biophysical membrane-centric perspective. Cancer Res. 2021 Jan 15;81(2):237–247. doi: 10.1158/0008-5472.CAN-20-0911
  • Iida M, Harari PM, Wheeler DL, et al. Targeting AKT/PKB to improve treatment outcomes for solid tumors. Mutat Res. 2020;819-820:111690. doi: 10.1016/j.mrfmmm.2020.111690
  • Liu X, Zhou Q, Hart JR, et al. Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3Kα. Proc Natl Acad Sci, USA. 2022;119(46):e2215621119. doi: 10.1073/pnas.2215621119
  • Fusco N, Malapelle U, Fassan M, et al. PIK3CA mutations as a molecular target for hormone receptor-positive, HER2-negative metastatic breast cancer. Front Oncol. 2021;11:644737. doi: 10.3389/fonc.2021.644737
  • Liu R, Chen Y, Liu G, et al. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis. 2020;11(9):797. doi: 10.1038/s41419-020-02998-6
  • Hajjo R, Sabbah DA, Abusara OH, et al. Targeting human proteins for antiviral drug discovery and repurposing efforts: a focus on protein kinases. Viruses. 2023;15(2):568. doi: 10.3390/v15020568
  • Matsuda S, Ikeda Y, Murakami M, et al. Roles of PI3K/AKT/GSK3 pathway involved in psychiatric illnesses. Diseases. 2019;7(1):22. doi: 10.3390/diseases7010022
  • Razani E, Pourbagheri-Sigaroodi A, Safaroghli-Azar A, et al. The PI3K/Akt signaling axis in Alzheimer’s disease: a valuable target to stimulate or suppress? Cell Stress Chaperones. 2021;26(6):871–887. doi: 10.1007/s12192-021-01231-3
  • Kumar M, Bansal N. Implications of phosphoinositide 3-kinase-akt (PI3K-Akt) pathway in the pathogenesis of Alzheimer’s disease. Mol Neurobiol. 2022;59(1):354–385. doi: 10.1007/s12035-021-02611-7
  • Curtis D, Bandyopadhyay S. Mini-review: role of the PI3K/Akt pathway and tyrosine phosphatases in Alzheimer’s disease susceptibility. Ann Hum Genet. 2021;85(1):1–6. doi: 10.1111/ahg.12410
  • Clarivate. Introducing cortellis drug discovery intelligence [cited 2023 Jul 25]. Available from: https://clarivate.com/cortellis/campaigns/introducing-cortellis-drug-discovery-intelligence/#Clarivate
  • Hopkins BD, Goncalves MD, Cantley LC. Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nat Rev Endocrinol. 2020;16(5):276–283. doi: 10.1038/s41574-020-0329-9
  • Donato J Jr., Frazão R, Elias CF. The PI3K signaling pathway mediates the biological effects of leptin. Arq Bras Endocrinol Metabol. 2010;54(7):591–602. doi: 10.1590/s0004-27302010000700002
  • Daragmeh J, Barriah W, Saad B, et al. Analysis of PI3K pathway components in human cancers. Oncol Lett. 2016;11(4):2913–2918. doi: 10.3892/ol.2016.4309
  • Zhang Z, Richmond A. The role of PI3K inhibition in the treatment of breast cancer, alone or combined with immune checkpoint inhibitors. Front Mol Biosci. 2021;8:648663. doi: 10.3389/fmolb.2021.648663
  • Sala V, Della Sala A, Ghigo A, et al. Roles of phosphatidyl inositol 3 kinase gamma (PI3Kγ) in respiratory diseases. Cell Stress. 2021;5(4):40–51. doi: 10.15698/cst2021.04.246
  • Rascio F, Spadaccino F, Rocchetti MT, et al. The pathogenic role of PI3K/AKT pathway in cancer onset and drug resistance: an updated review. Cancers (Basel). 2021;13(16):3949. doi: 10.3390/cancers13163949
  • Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169(3):381–405. doi: 10.1016/j.cell.2017.04.001
  • Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020;20(2):74–88. doi: 10.1038/s41568-019-0216-7
  • Vanhaesebroeck B, Whitehead MA, Piñeiro R. Molecules in medicine mini-review: isoforms of PI3K in biology and disease. J Mol Med. 2016;94(1):5–11. doi: 10.1007/s00109-015-1352-5
  • Vasan N, Toska E, Scaltriti M. Overview of the relevance of PI3K pathway in HR-positive breast cancer. Ann Oncol. 2019;30(Suppl_10):x3–x11. doi: 10.1093/annonc/mdz281
  • Yang J, Nie J, Ma X, et al. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer. 2019;18(1):26. doi: 10.1186/s12943-019-0954-x
  • Martorana F, Motta G, Pavone G, et al. AKT inhibitors: New weapons in the fight against breast cancer? Front Pharmacol. 2021;12:662232. doi: 10.3389/fphar.2021.662232
  • Dunn S, Eberlein C, Yu J, et al. AKT-mTORC1 reactivation is the dominant resistance driver for PI3Kβ/AKT inhibitors in PTEN-null breast cancer and can be overcome by combining with Mcl-1 inhibitors. Oncogene. 2022;41(46):5046–5060. doi: 10.1038/s41388-022-02482-9
  • Pazarentzos E, Giannikopoulos P, Hrustanovic G, et al. Oncogenic activation of the PI3-kinase p110β isoform via the tumor-derived PIK3Cβ(D1067V) kinase domain mutation. Oncogene. 2016;35(9):1198–1205. doi: 10.1038/onc.2015.173
  • Owusu-Brackett N, Zhao M, Akcakanat A, et al. Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss. Oncotarget. 2020;11(11):969–981. doi: 10.18632/oncotarget.27503
  • Talwelkar SS, Mäyränpää MI, Schüler J, et al. PI3Kβ inhibition enhances ALK-inhibitor sensitivity in ALK-rearranged lung cancer. Mol Oncol. 2023;17(5):747–764. doi: 10.1002/1878-0261.13342
  • Tzenaki N, Andreou M, Stratigi K, et al. High levels of p110δ PI3K expression in solid tumor cells suppress PTEN activity, generating cellular sensitivity to p110δ inhibitors through PTEN activation. Faseb J. 2012;26(6):2498–2508. doi: 10.1096/fj.11-198192
  • Tarantelli C, Argnani L, Zinzani PL, et al. PI3Kδ inhibitors as immunomodulatory agents for the treatment of lymphoma patients. Cancers (Basel). 2021;13(21):5535. doi: 10.3390/cancers13215535
  • Schmid MC, Avraamides CJ, Dippold HC, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 2011;19(6):715–727. doi: 10.1016/j.ccr.2011.04.016
  • Gonzalez E, McGraw TE. The Akt kinases: isoform specificity in metabolism and cancer. Cell Cycle. 2009;8(16):2502–2508. doi: 10.4161/cc.8.16.9335
  • Hinz N, Jücker M. Distinct functions of AKT isoforms in breast cancer: a comprehensive review. Cell Commun Signal. 2019;17(1):154. doi: 10.1186/s12964-019-0450-3
  • Chen WS, Xu PZ, Gottlob K, et al. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev. 2001;15(17):2203–2208. doi: 10.1101/gad.913901
  • Garofalo RS, Orena SJ, Rafidi K, et al. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest. 2003;112(2):197–208.
  • Cho H, Mu J, Kim JK, et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ). Science. 2001;292(5522):1728–1731. doi: 10.1126/science.292.5522.1728
  • Tschopp O, Yang ZZ, Brodbeck D, et al. Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development. 2005;132(13):2943–2954.
  • Peng XD, Xu PZ, Chen ML, et al. Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev. 2003;17(11):1352–1365. doi: 10.1101/gad.1089403
  • Kim J, Guan KL. mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol. 2019;21(1):63–71. doi: 10.1038/s41556-018-0205-1
  • Oleksak P, Nepovimova E, Chrienova Z, et al. Contemporary mTOR inhibitor scaffolds to diseases breakdown: A patent review (2015-2021). Eur J Med Chem. 2022;238:114498. doi: 10.1016/j.ejmech.2022.114498
  • Yi KH, Lauring J. Recurrent AKT mutations in human cancers: functional consequences and effects on drug sensitivity. Oncotarget. 2016;7(4):4241–4251. doi: 10.18632/oncotarget.6648
  • Liu T, Zhu J, Du W, et al. AKT2 drives cancer progression and is negatively modulated by miR-124 in human lung adenocarcinoma. Respir Res. 2020;21(1):227. doi: 10.1186/s12931-020-01491-0
  • Pereira L, Horta S, Mateus R, et al. Implications of Akt2/Twist crosstalk on breast cancer metastatic outcome. Drug Discov Today. 2015;20(9):1152–1158. doi: 10.1016/j.drudis.2015.06.010
  • Sahlberg SH, Gustafsson AS, Pendekanti PN, et al. The influence of AKT isoforms on radiation sensitivity and DNA repair in colon cancer cell lines. Tumour Biol. 2014;35(4):3525–3534. doi: 10.1007/s13277-013-1465-9
  • Buikhuisen JY, Gomez Barila PM, Torang A, et al. AKT3 expression in mesenchymal colorectal cancer cells drives growth and is associated with epithelial-mesenchymal transition. Cancers (Basel). 2021;13(4):801. doi: 10.3390/cancers13040801
  • Takahashi H, Rokudai S, Kawabata-Iwakawa R, et al. AKT3 is a novel regulator of cancer-associated fibroblasts in head and neck squamous cell carcinoma. Cancers (Basel). 2021;13(6):1233. doi: 10.3390/cancers13061233
  • Chang CZ, Wu SC, Chang CM, et al. Arctigenin, a potent ingredient of Arctium lappa L. induces endothelial nitric oxide synthase and attenuates subarachnoid hemorrhage-induced vasospasm through PI3K/Akt pathway in a rat model. Biomed Res Int. 2015;2015:490209. doi: 10.1155/2015/490209
  • Yu H, Lin L, Zhang Z, et al. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther. 2020;5(1):209. doi: 10.1038/s41392-020-00312-6
  • Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 2013;12(1):86. doi: 10.1186/1476-4598-12-86
  • Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci. 2011;4:51. doi: 10.3389/fnmol.2011.00051
  • Jafari M, Ghadami E, Dadkhah T, et al. PI3k/AKT signaling pathway: erythropoiesis and beyond. J Cell Physiol. 2019;234(3):2373–2385. doi: 10.1002/jcp.27262
  • Ediriweera MK, Tennekoon KH, Samarakoon SR. Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: Biological and therapeutic significance. Semin Cancer Biol. 2019;59:147–160. doi: 10.1016/j.semcancer.2019.05.012
  • Ghoneum A, Said N. PI3K-AKT-mTOR and NFκB pathways in ovarian cancer: implications for targeted therapeutics. Cancers (Basel). 2019;11(7):949. doi: 10.3390/cancers11070949
  • Deng J, Bai X, Feng X, et al. Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression. BMC Cancer. 2019;19(1):618. doi: 10.1186/s12885-019-5824-9
  • Mabuchi S, Kuroda H, Takahashi R, et al. The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer. Gynecol Oncol. 2015;137(1):173–179. doi: 10.1016/j.ygyno.2015.02.003
  • Citi V, Del Re M, Martelli A, et al. Phosphorylation of AKT and ERK1/2 and mutations of PIK3CA and PTEN are predictive of breast cancer cell sensitivity to everolimus in vitro. Cancer Chemother Pharmacol. 2018;81(4):745–754. doi: 10.1007/s00280-018-3543-6
  • Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68(15):6084–6091. doi: 10.1158/0008-5472.CAN-07-6854
  • Hafsi S, Pezzino FM, Candido S, et al. Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance (review). Int J Oncol. 2012;40(3):639–644. doi: 10.3892/ijo.2011.1312
  • Braglia L, Zavatti M, Vinceti M, et al. Deregulated PTEN/PI3K/AKT/mTOR signaling in prostate cancer: still a potential druggable target?. Biochim Biophys Acta Mol Cell Res. 2020;1867(9):118731. doi: 10.1016/j.bbamcr.2020.118731
  • Vanhaesebroeck B, Perry MWD, Brown JR, et al. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov. 2021;20(10):741–769. doi: 10.1038/s41573-021-00209-1
  • Jiang N, Dai Q, Su X, et al. Role of PI3K/AKT pathway in cancer: the framework of malignant behavior. Mol Biol Rep. 2020;47(6):4587–4629. doi: 10.1007/s11033-020-05435-1
  • Zhang M, Jang H, Nussinov R. PI3K inhibitors: review and new strategies. Chem Sci. 2020;11(23):5855–5865. doi: 10.1039/d0sc01676d
  • Meng D, He W, Zhang Y, et al. Development of PI3K inhibitors: Advances in clinical trials and new strategies (Review). Pharmacol Res. 2021;173:105900. doi: 10.1016/j.phrs.2021.105900
  • Fuso P, Muratore M, D’Angelo T, et al. PI3K inhibitors in advanced breast cancer: The past, the present, new challenges and future perspectives. Cancers. 2022;14(9):2161. doi: 10.3390/cancers14092161
  • Durrant TN, Hers I. PI3K inhibitors in thrombosis and cardiovascular disease. Clin Transl Med. 2020;9(1):8. doi: 10.1186/s40169-020-0261-6
  • Zhu J, Li K, Yu L, et al. Targeting phosphatidylinositol 3-kinase gamma (PI3Kγ): discovery and development of its selective inhibitors. Med Res Rev. 2021;41(3):1599–1621. doi: 10.1002/med.21770
  • Occhiuzzi MA, Lico G, Ioele G, et al. Recent advances in PI3K/PKB/mTOR inhibitors as new anticancer agents. Eur J Med Chem. 2023;246:114971. doi: 10.1016/j.ejmech.2022.114971
  • Dienstmann R, Rodon J, Serra V, et al. Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther. 2014;13(5):1021–1031. doi: 10.1158/1535-7163.MCT-13-0639
  • Wu X, Xu Y, Liang Q, et al. Recent advances in dual PI3K/mTOR inhibitors for tumour treatment. Front Pharmacol. 2022;13:875372. doi: 10.3389/fphar.2022.875372
  • Das D, Wang J, Hong J. Next-generation kinase inhibitors targeting specific biomarkers in non-small cell lung cancer (NSCLC): a recent overview. ChemMedchem. 2021 Aug 19;16(16):2459–2479. doi: 10.1002/cmdc.202100166
  • Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4(11):682–690. doi: 10.1038/nchembio.118
  • Hajjo R, Setola V, Roth BL, et al. Chemocentric informatics approach to drug discovery: identification and experimental validation of selective estrogen receptor modulators as ligands of 5-hydroxytryptamine-6 receptors and as potential cognition enhancers. J Med Chem. 2012;55(12):5704–5719. doi: 10.1021/jm2011657
  • STRING| Protein-Protein Interaction Networks| Functional Enrichment Analysis. [cited 2023 Jul 21]. Available from: https://string-db.org/
  • Cytoscape Version 3.10.0.| Network Data Integration, Analysis, and Visualization in a Box. [cited 2023 Jul 21]. Available from: https://cytoscape.org/
  • KEGG: Kyoto Encyclopedia of Genes and Genomes. [cited 2023 Jul 21]. Available from: https://www.genome.jp/kegg/.
  • ClinicalTrials.gov. Available from: https://classic.clinicaltrials.gov/ct2/home.
  • Tanaka H, Yoshida M, Tanimura H, et al. The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011;17(10):3272–3281. doi: 10.1158/1078-0432.CCR-10-2882
  • Blagden S, Omlin A, Josephs D, et al. First-in-human study of CH5132799, an oral class I PI3K inhibitor, studying toxicity, pharmacokinetics, and pharmacodynamics, in patients with metastatic cancer. Clin Cancer Res. 2014;20(23):5908–5917.
  • Tosca EM, Borella E, Piana C, et al. Model-based prediction of effective target exposure for MEN1611 in combination with trastuzumab in HER2-positive advanced or metastatic breast cancer patients. CPT Pharmacometrics Syst Pharmacol. 2023;12(11):1626–1639. doi: 10.1002/psp4.12910
  • Guillermet-Guibert J. Methods for the prophylactic treatment of cancer in patients suffering from pancreatitis using PI3Kα inhibitors. World Patent WO 2021/001427 A1. published 2021 Jan 7.
  • Doukas J, Wrasidlo W, Noronha G, et al. Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury. Proc Natl Acad Sci USA. 2006;103(52):19866–19871.
  • Song C, Bae Y, Jun J, et al. Identification of TG100-115 as a new and potent TRPM7 kinase inhibitor, which suppresses breast cancer cell migration and invasion. Biochim Biophys Acta Gen Subj. 2017;1861(4):947–957. doi: 10.1016/j.bbagen.2017.01.034
  • Mishra R, Yuan L, Patel H, et al. Phosphoinositide 3-kinase (PI3K) reactive oxygen species (ROS)-activated prodrug in combination with anthracycline impairs PI3K signaling, increases DNA damage response and reduces breast cancer cell growth. Int J Mol Sci. 2021;22(4):2088. doi: 10.3390/ijms22042088
  • Westhoff MA, Kandenwein JA, Karl S, et al. The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair. Oncogene. 2009;28(40):3586–3596. doi: 10.1038/onc.2009.215
  • Patel H, Mishra R, Wier A, et al. RIDR-PI-103, ROS-activated prodrug PI3K inhibitor inhibits cell growth and impairs the PI3K/Akt pathway in BRAF and MEK inhibitor-resistant BRAF-mutant melanoma cells. Anticancer Drugs. 2023;34(4):519–531. doi: 10.1097/CAD.0000000000001500
  • Zhu H, Mishra R, Yuan L, et al. Oxidative cyclization-induced activation of a phosphoinositide 3-kinase inhibitor for enhanced selectivity of cancer chemotherapeutics. ChemMedchem. 2019;14(22):1933–1939. doi: 10.1002/cmdc.201900481
  • Luo L, Zhong Q, Guo S, et al. Development of a bioavailable boron-containing PI-103 bioisostere, PI-103BE. Bioorg Med Chem Lett. 2020;30(14):127258. doi: 10.1016/j.bmcl.2020.127258
  • Sutherlin DP, Bao L, Berry M, et al. Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J Med Chem. 2011;54(21):7579–7587. doi: 10.1021/jm2009327
  • Omeljaniuk WJ, Krętowski R, Ratajczak-Wrona W, et al. Novel dual PI3K/mTOR inhibitor, apitolisib (GDC-0980), inhibits growth and induces apoptosis in human glioblastoma cells. Int J Mol Sci. 2021;22(21):11511. doi: 10.3390/ijms222111511
  • Makker V, Recio FO, Ma L, et al. A multicenter, single-arm, open-label, phase 2 study of apitolisib (GDC-0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study). Cancer. 2016;122(22):3519–3528. doi: 10.1002/cncr.30286
  • Dolly SO, Wagner AJ, Bendell JC, et al. Phase I study of apitolisib (GDC-0980), dual phosphatidylinositol-3-kinase and mammalian target of rapamycin kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2016;22(12):2874–2884. doi: 10.1158/1078-0432.CCR-15-2225
  • Powles T, Lackner MR, Oudard S, et al. Randomized open-label phase II trial of apitolisib (GDC-0980), a novel inhibitor of the PI3K/mammalian target of rapamycin pathway, versus everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2016;34(14):1660–1668. doi: 10.1200/JCO.2015.64.8808
  • Johnson F, Frederick MJ, Treatment of squamous cell carcinoma with phosphatidylinositol 3-kinase (PI3K) inhibitors. United States Patent US 2020/0248273 A1. published 2020 Aug 6.
  • Maddocks ODK, Young T, Goncalves MD, Combination therapy for PIK3CA-associated diseases or disorders. World Patent WO 2023/070023 Al. published 2023 April 27.
  • Gunst JD, Kjær K, Olesen R, et al. Fimepinostat, a novel dual inhibitor of HDAC and PI3K, effectively reverses HIV-1 latency ex vivo without T cell activation. J Virus Erad. 2019;5(3):133–137. doi: 10.1016/S2055-6640(20)30042-X
  • Huegel J, Dinh CT, Martinelli M, et al. CUDC907, a dual phosphoinositide-3 kinase/histone deacetylase inhibitor, promotes apoptosis of NF2 schwannoma cells. Oncotarget. 2022;13(1):890–904. doi: 10.18632/oncotarget.28254
  • Chen J, Guanizo AC, Jakasekara WSN, et al. MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat. J Exp Clin Cancer Res. 2023;42(1):100. doi: 10.1186/s13046-023-02678-1
  • Liao W, Yang W, Xu J, et al. Therapeutic potential of CUDC-907 (fimepinostat) for hepatocarcinoma treatment revealed by tumor spheroids-based drug screening. Front Pharmacol. 2021;12:658197. doi: 10.3389/fphar.2021.658197
  • Landsburg DJ, Barta SK, Ramchandren R, et al. Fimepinostat (CUDC-907) in patients with relapsed/refractory diffuse large B cell and high-grade B-cell lymphoma: report of a phase 2 trial and exploratory biomarker analyses. Br J Haematol. 2021;195(2):201–209. doi: 10.1111/bjh.17730
  • Barkund S, Zhou H, Friedman L, et al., Uses of glucocorticoid receptor (GR) antagonist, antiandrogen, and AKT inhibitor/PI3K inhibitor/mTOR inhibitor combinations. World Patent WO 2022/192182 A2. published 2022 Sept 15.
  • Fairhurst RA, Furet P, Imbach-Weese P, et al. Identification of NVP-CLR457 as an orally bioavailable non-cns-penetrant pan-class ia phosphoinositol-3-kinase inhibitor. J Med Chem. 2022;65(12):8345–8379. doi: 10.1021/acs.jmedchem.2c00267
  • Harding JJ, Bauer TM, Tan DSW, et al. Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor. Invest New Drugs. 2019;37(2):271–281. doi: 10.1007/s10637-018-0627-4
  • Wang W, Liao L, Wang Y, et al. Preclinical evaluation of novel PI3K/mTOR dual inhibitor SN202 as potential anti-renal cancer agent. Cancer Biol Ther. 2018;19(11):1015–1022. doi: 10.1080/15384047.2018.1470733
  • Beaufils F, Cmiljanovic N, Cmiljanovic V, et al. 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor as clinical candidate in oncology. J Med Chem. 2017;60(17):7524–7538. doi: 10.1021/acs.jmedchem.7b00930
  • Collins GP, Eyre TA, Schmitz-Rohmer D, et al. A phase II study to assess the safety and efficacy of the dual mTORC1/2 and PI3K inhibitor bimiralisib (PQR309) in relapsed, refractory lymphoma. Hemasphere. 2021;5(11):e656. doi: 10.1097/HS9.0000000000000656
  • Johnson FM, Janku F, Gouda MA, et al. Inhibition of the phosphatidylinositol-3 kinase pathway using bimiralisib in loss-of-function NOTCH1-mutant head and neck cancer. Oncology. 2022;27(12):1004–e926. doi: 10.1093/oncolo/oyac185
  • Rolli M, Schmitz-Rohmer D, Fabbro D, et al. Treatment of squamous cell carcinoma. World Patent WO2020030708. 2019 Aug 7.
  • Sabbah DA, Vennerstrom JL, Zhong HA. Binding selectivity studies of phosphoinositide 3-kinases using free energy calculations. J Chem Inf Model. 2012;52(12):3213–3224. doi: 10.1021/ci3003057
  • Al Hasan M, Sabirianov M, Redwine G, et al. Binding and selectivity studies of phosphatidylinositol 3-kinase (PI3K) inhibitors. J Mol Graph Model. 2023 Jun;121:108433. doi: 10.1016/j.jmgm.2023.108433
  • Borsari C, Wymann M Method for identifying PI3 kinase-α inhibitors. World Patent WO 2022/214703 A2. published 2022 Oct 13.
  • St. Jean JD. Compounds that inhibit PI3K isoform alpha and methods for treating cancer. World Patent WO 2023/018636 Al. published 2023 Feb 16.
  • Chang KY, Tsai SY, Wu CM, et al. Novel phosphoinositide 3-kinase/mTOR dual inhibitor, NVP-BGT226, displays potent growth-inhibitory activity against human head and neck cancer cells in vitro and in vivo. Clin Cancer Res. 2011;17(22):7116–7126. doi: 10.1158/1078-0432.CCR-11-0796
  • Simioni C, Cani A, Martelli AM, et al. The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells. Oncotarget. 2015;6(19):17147–17160. doi: 10.18632/oncotarget.3940
  • Glienke W, Maute L, Wicht J, et al. The dual PI3K/mTOR inhibitor NVP-BGT226 induces cell cycle arrest and regulates survivin gene expression in human pancreatic cancer cell lines. Tumour Biol. 2012;33(3):757–765. doi: 10.1007/s13277-011-0290-2
  • Wang L, Che Y, Yijing L, et al. Pharmaceutical combination comprising abemaciclib and a PI3K and/or a mtor inhibitor for the treatment of mantle cell lymphoma. World Patent WO 2023/114225 A1. published 2023 June 22
  • Cheng H, Li C, Bailey S, et al. Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04979064 through structure-based drug design. ACS Med Chem Lett. 2013;4(1):91–97. doi: 10.1021/ml300309h
  • Han J, Chen Y, Yang C, et al. Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor. Eur J Med Chem. 2016;122:684–701. doi: 10.1016/j.ejmech.2016.06.030
  • Choi HJ, Heo JH, Park JY, et al. A novel PI3K/mTOR dual inhibitor, CMG002, overcomes the chemoresistance in ovarian cancer. Gynecol Oncol. 2019;153(1):135–148. doi: 10.1016/j.ygyno.2019.01.012
  • Kim MN, Lee SM, Kim JS, et al. Preclinical efficacy of a novel dual PI3K/mTOR inhibitor, CMG002, alone and in combination with sorafenib in hepatocellular carcinoma. Cancer Chemother Pharmacol. 2019;84(4):809–817. doi: 10.1007/s00280-019-03918-y
  • Kim MY, Kruger AJ, Jeong JY, et al. Combination therapy with a PI3K/mTOR dual inhibitor and chloroquine enhances synergistic apoptotic cell death in Epstein-Barr virus-infected gastric cancer cells. Mol Cells. 2019;42(6):448–459.
  • Hanan EJ, Braun MG, Heald RA, et al. Discovery of GDC-0077 (inavolisib), a highly selective inhibitor and degrader of mutant PI3Kα. J Med Chem. 2022;65(24):16589–16621. doi: 10.1021/acs.jmedchem.2c01422
  • Song KW, Edgar KA, Hanan EJ, et al. RTK-dependent inducible degradation of mutant PI3Kα drives GDC-0077 (inavolisib) efficacy. Cancer Discov. 2022;12(1):204–219. doi: 10.1158/2159-8290.CD-21-0072
  • Vasan N, Baselga J Biomarkers for determining responsiveness of a cancer to phosphatidylinositol 3-kinase (PI3K) inhibitors. World Patent WO 2020/041684 A1. published 2020 Feb 27.
  • Hong DS, Postow M, Chmielowski B, et al. Eganelisib, a first-in-class PI3Kγ inhibitor, in patients with advanced solid tumors: results of the phase 1/1b MARIO-1 trial. Clin Cancer Res. 2023;29(12):2210–2219. doi: 10.1158/1078-0432.CCR-22-3313
  • Faehling S, Coelho M, Floerchinger A, et al. Simultaneous inhibition of PI3Kgamma and PI3Kdelta deteriorates T-cell function with implications for chronic lymphocytic leukemia. Hemasphere. 2023 Mar;7(3):e840. doi: 10.1097/HS9.0000000000000840
  • Xu Y, Afify SM, Du J, et al. The efficacy of PI3Kγ and EGFR inhibitors on the suppression of the characteristics of cancer stem cells. Sci Rep. 2022;12(1):347. doi: 10.1038/s41598-021-04265-w
  • Sun D, Gao W, Wen F, et al. PI3K inhibitors, nanoformulations, and uses thereof. World Patent WO 2022/226052 A1. published 2022 Oct 27.
  • O´connell BC Eganelisib for use in the treatment of PD-L1 negative cancer. World Patent WO 2022/125497 A1. published 2022 June 16.
  • Kong D, Yamori T. Phosphatidylinositol 3-kinase inhibitors: promising drug candidates for cancer therapy. Cancer Sci. 2008;99(9):1734–1740. doi: 10.1111/j.1349-7006.2008.00891.x
  • Azzi J, Moore RF, Elyaman W, et al. The novel therapeutic effect of phosphoinositide 3-kinase-γ inhibitor AS605240 in autoimmune diabetes. Diabetes. 2012;61(6):1509–1518. doi: 10.2337/db11-0134
  • Sun J, Cai G, Shen J, et al. AS-605240 blunts osteoporosis by inhibition of bone resorption. Drug Des Devel Ther. 2023;17:1275–1288. doi: 10.2147/DDDT.S403231
  • Li M, Sala V, De Santis MC, et al. Phosphoinositide 3-kinase gamma inhibition protects from anthracycline cardiotoxicity and reduces tumor growth. Circulation. 2018;138(7):696–711. doi: 10.1161/CIRCULATIONAHA.117.030352
  • Kong W, Sender S, Taher L, et al. BTK and PI3K inhibitors reveal synergistic inhibitory anti-tumoral effects in canine diffuse large b-cell lymphoma cells. Int J Mol Sci. 2021;22(23):12673. doi: 10.3390/ijms222312673
  • Gao B, Wang L, Zhang N, et al. Screening novel drug candidates for kidney renal clear cell carcinoma treatment: a study on differentially expressed genes through the connectivity map database. Kidney Blood Press Res. 2021;46(6):702–713. doi: 10.1159/000518437
  • Alluri R, Ambati SR, Routhu K, et al. Phosphoinositide 3-kinase inhibitor AS605240 ameliorates streptozotocin-induced Alzheimer’s disease like sporadic dementia in experimental rats. EXCLI J. 2020;19:71–85. doi: 10.17179/excli2019-1997
  • Garces AE, Stocks MJ. Class 1 PI3K clinical candidates and recent inhibitor design strategies: a medicinal chemistry perspective. J Med Chem. 2019;62(10):4815–4850. doi: 10.1021/acs.jmedchem.8b01492
  • Ali AY, Wu X, Eissa N, et al. Distinct roles for phosphoinositide 3-kinases γ and δ in malignant B cell migration. Leukemia.2018 Sep;32(9):1958–1969.
  • Piddock RE, Loughran N, Marlein CR, et al. PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment. Blood Cancer J. 2017 Mar 10;7(3):e539. doi: 10.1038/bcj.2017.16
  • Wang Z, Hao Y, Li Y Compositions and methods of treating PIK3CA helical domain mutant cancers. United States Patent US 2022/0193056 A1. published 2022 June 23
  • Pemberton N, Mogemark M, Arlbrandt S, et al. Discovery of highly isoform selective orally bioavailable phosphoinositide 3-kinase (PI3K)-γ inhibitors. J Med Chem. 2018;61(12):5435–5441. doi: 10.1021/acs.jmedchem.8b00447
  • Carnevalli LS, Taylor MA, King M, et al. Macrophage activation status rather than repolarization is associated with enhanced checkpoint activity in combination with PI3Kγ inhibition. Mol Cancer Ther. 2021;20(6):1080–1091. doi: 10.1158/1535-7163.MCT-20-0961
  • Safina BS, Sweeney ZK, Li J, et al. Identification of GNE-293, a potent and selective PI3Kδ inhibitor: navigating in vitro genotoxicity while improving potency and selectivity. Bioorg Med Chem Lett. 2013;23(17):4953–4959. doi: 10.1016/j.bmcl.2013.06.052
  • Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058–2070.
  • Shi Z, Wulfkuhle J, Nowicka M, et al. Functional mapping of AKT signaling and biomarkers of response from the FAIRLANE trial of neoadjuvant ipatasertib plus paclitaxel for triple-negative breast cancer. Clin Cancer Res. 2022;28(5):993–1003. doi: 10.1158/1078-0432.CCR-21-2498
  • Spencer A, Yoon SS, Harrison SJ, et al. The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood. 2014;124(14):2190–2195. doi: 10.1182/blood-2014-03-559963
  • Ragon BK, Odenike O, Baer MR, et al. Oral MEK 1/2 inhibitor trametinib in combination with AKT inhibitor GSK2141795 in patients with acute myeloid leukemia with RAS mutations: a phase II study. Clin Lymphoma Myeloma Leuk. 2019;19(7):431–40.e13. doi: 10.1016/j.clml.2019.03.015
  • Levy DS, Kahana JA, Kumar R. AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood. 2009;113(8):1723–1729. doi: 10.1182/blood-2008-02-137737
  • Weisner J, Gontla R, van der Westhuizen L, et al. Covalent-allosteric kinase inhibitors. Angew Chem Int Ed Engl. 2015;54(35):10313–10316. doi: 10.1002/anie.201502142
  • Hirai H, Sootome H, Nakatsuru Y, et al. MK-2206, an allosteric akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther. 2010;9(7):1956–1967. doi: 10.1158/1535-7163.MCT-09-1012
  • Deng X Inhibitors of MCL-1 domain and AKT domain interaction and uses thereof for the treatment of cancer. United States Patent US20210137953A1. published 2021 May 13
  • Huang J, Chen L, Wu J, et al. Targeting the PI3K/AKT/mTOR signaling pathway in the treatment of human diseases: current status, trends, and solutions. J Med Chem. 2022 Dec 22;65(24):16033–16061. doi: 10.1021/acs.jmedchem.2c01070
  • Howell SJ, Casbard A, Carucci M, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial. Lancet Oncol. 2022 Jul;23(7):851–864.
  • Crabb SJ, Griffiths G, Marwood E, et al. Pan-AKT Inhibitor capivasertib with docetaxel and prednisolone in metastatic castration-resistant prostate cancer: A randomized, placebo-controlled phase ii trial (ProCAID). J Clin Oncol. 2021 Jan 20;39(3):190–201. doi: 10.1200/JCO.20.01576
  • Floch N, Martin M, Joseph S, et al. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in combination with an AKT inhibitor for the treatment of cancer. World Patent WO 2023/187037 A1, published 2023 Oct 5.
  • Turner N, Dent RA, O’Shaughnessy J, et al. Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial. Breast Cancer Res Treat. 2022;191(3):565–576. doi: 10.1007/s10549-021-06450-x
  • Sweeney C, Bracarda S, Sternberg CN, et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2021;398(10295):131–142. doi: 10.1016/S0140-6736(21)00580-8
  • Withana NP, Mani A, Singel SM Treatment of breast cancer using combination therapies comprising an AKT inhibitor, a taxane, and a PD-l1 inhibitor. World Patent WO 2020/131765 A1. published 2020 Jun 25.
  • Gray N, You I, Zhang T Degradation of AKT by conjugation of ATP-competitive AKT inhibitor GDC-0068 with E3 ligase ligands and methods of use. World Patent WO 2020/0226481 A1. published 2020 Oct 15.
  • Lu C, Zhang R, Yu Y, et al. Methods of treating prostate cancer in a patient using combination of afuresertib and CFG920. World Patent WO 2021/026454 A1, published 2021 Feb 11.
  • Wee S, Jagani Z, Xiang KX, et al. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 2009;69(10):4286–4293. doi: 10.1158/0008-5472.CAN-08-4765
  • Liu JF, Gray KP, Wright AA, et al. Results from a single arm, single stage phase II trial of trametinib and GSK2141795 in persistent or recurrent cervical cancer. Gynecol Oncol. 2019;154(1):95–101. doi: 10.1016/j.ygyno.2019.05.003
  • Shen Z, Kin K AKT inhibitor in combination with PIM kinase inhibitor. World Patent WO 2023/202563 A1. published 2023 Oct 26.
  • Ma C, Wu J, Wang L, et al. Discovery of clinical candidate NTQ1062 as a potent and bioavailable akt inhibitor for the treatment of human tumors. J Med Chem. 2022;65(12):8144–8168. doi: 10.1021/acs.jmedchem.2c00527
  • Che J, Dai X, Gao J, et al. Discovery of N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (Hu7691), a potent and selective Akt inhibitor that enables decrease of cutaneous toxicity. J Med Chem. 2021;64(16):12163–12180. doi: 10.1021/acs.jmedchem.1c00815
  • Landel I, Quambusch L, Depta L, et al. Spotlight on AKT: Current therapeutic challenges. ACS Med Chem Lett. 2020;11(3):225–227. doi: 10.1021/acsmedchemlett.9b00548
  • Chien AJ, Tripathy D, Albain KS, et al. MK-2206 and standard neoadjuvant chemotherapy improves response in patients with human epidermal growth factor receptor 2-positive and/or hormone receptor-negative breast cancers in the I-SPY 2 trial. J Clin Oncol. 2020;38(10):1059–1069.
  • Murphy AG, Zahurak M, Shah M, et al. A Phase I study of dinaciclib in combination with MK-2206 in patients with advanced pancreatic cancer. Clin Transl Sci. 2020;13(6):1178–1188. doi: 10.1111/cts.12802
  • Wood K, Lin KH, Rutter J, et al. Compositions and methods for sensitizing acute myeloid leukemias to chemotherapy. World Patent WO 2021/242859 A1. published 2021 Dec 2.
  • Yu Y, Savage RE, Eathiraj S, et al. Targeting AKT1-E17K and the PI3K/AKT Pathway with an Allosteric AKT Inhibitor, ARQ 092. PLoS One. 2015;10(10):e0140479. doi: 10.1371/journal.pone.0140479
  • Le Cras TD, Goines J, Lakes N, et al. Constitutively active PIK3CA mutations are expressed by lymphatic and vascular endothelial cells in capillary lymphatic venous malformation. Angiogenesis. 2020;23(3):425–442. doi: 10.1007/s10456-020-09722-0
  • Biesecker LG, Edwards M, O’Donnell S, et al. Clinical report: one year of treatment of Proteus syndrome with miransertib (ARQ 092). Cold Spring Harb Mol Case Stud. 2020;6(1):a004549. doi: 10.1101/mcs.a004549
  • Taunton J, Craven GB, Reisberg SH, et al. Preparation of substituted 3-(imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines as covalent modifiers of AKT1 and uses thereof. World Patent WO 2023/168291 A1. published 2023 Sept 7.
  • Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327(5971):1345–1350. doi: 10.1126/science.1177319
  • Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2017;16(2):101–114. doi: 10.1038/nrd.2016.211
  • Xu J, Yu X, Martin TC, et al. AKT degradation selectively inhibits the growth of PI3K/PTEN pathway-mutant cancers with wild-type KRAS and BRAF by destabilizing aurora kinase B. Cancer Discov. 2021;11(12):3064–3089.
  • You I, Erickson EC, Donovan KA, et al. Discovery of an AKT Degrader with prolonged inhibition of downstream signaling. Cell Chem Biol. 2020;27(1):66–73.e7. doi: 10.1016/j.chembiol.2019.11.014
  • He M, Cao C, Ni Z, et al. Protacs: great opportunities for academia and industry (an update from 2020 to 2021). Signal Transduct Target Ther. 2022;7(1):181. doi: 10.1038/s41392-022-00999-9
  • Yu X, Xu J, Cahuzac KM, et al. Novel allosteric inhibitor-derived AKT proteolysis targeting chimeras (PROTACs) enable potent and selective AKT degradation in KRAS/BRAF mutant cells. J Med Chem. 2022;65(20):14237–14260. doi: 10.1021/acs.jmedchem.2c01454
  • Jauslin WT, Schild M, Schaefer T, et al. A high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Kα. Chem Sci. 2024;15(2):683–691. doi: 10.1039/d3sc04629j
  • Sabbah DA, Simms NA, Brattain MG, et al. Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases. Bioorg Med Chem Lett. 2012;22(2):876–880.
  • Cantley LC, Hopkins B, Mukherjee S, et al. Combination therapy for PI3K-associated disease or disorder. World Patent WO 2019/232403 Al. published 2019 Dec 5.
  • Zhong HA, Goodwin DT. Selectivity studies and free energy calculations of AKT inhibitors. Molecules. 2024;29(6):1233. doi: 10.3390/molecules29061233
  • Schmid P, Turner NC, Barrios CH, et al. First-line ipatasertib, atezolizumab, and taxane triplet for metastatic triple-negative breast cancer: clinical and biomarker results. Clin Cancer Res. 2024;30(4):767–778. doi: 10.1158/1078-0432.CCR-23-2084

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