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

ABSTRACT

Introduction

Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein–protein interaction networks for PI3K and AKT show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of PI3K/AKT in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of 35 inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions for developing combinational therapy and PROTACs of PI3K and AKT inhibitors are also discussed.

Area covered

This review covers clinical trial reports and patent literature on inhibitors of PI3K and AKT published between 2020 and 2023.

Expert opinion

To address drug resistance and drug toxicity of inhibitors of PI3K and AKT, it is highly desirable to design and develop subtype-selective PI3K inhibitors or subtype-selective AKT1 inhibitors to minimize toxicity or to develop allosteric drugs that can form covalent bonds. The development of PROTACs of PI3Kα or AKT helps to reduce off-target toxicities.

KEYWORDS:

• PI3K
• AKT
• covalent drugs
• anticancer
• selectivity
• combination therapy and PROTACs

Article highlights

• Covalent drugs containing an α,β-unsaturated amide moiety or aldehydes can form covalent bonds with target proteins.

• Selective AKT1 inhibitors can minimize adverse effects such as rash.

• Allosteric AKT inhibitors can overcome drug resistance.

• The synergy effect of inhibitors of PI3K and AKT with other drugs from different target proteins or different subtypes of the same protein shows improved efficacy and/or reduced adverse effect in different cancer.

• Proteolysis targeting chimeras (PROTACs) of PI3K or AKT degrade respective proteins and overcome acquired resistance with reduced toxicities.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author Contribution statement

All authors have contributed to the writing and revision of this manuscript.

Acknowledgments

R.H. and D.A.S. acknowledge support from the Deanship of Scientific Research at Al-Zaytoonah University of Jordan (Grant number 2020-2019/17/03).

Additional information

Funding

This paper was funded by the Deanship of Scientific Research at Al-Zaytoonah University of Jordan [Grant number 2020-2019/17/03].