Therapeutic potential of investigational CHK-1 inhibitors for the treatment of solid tumors

ABSTRACT

Introduction: For several decades’ cancer treatment targeting DNA repair pathways incorporated both chemo- and radiotherapy only. However, over the last decade improved knowledge of DNA repair processes has paved the way for the development of novel targeted drugs abrogating DNA repair signaling. Checkpoint kinase inhibitors are exciting molecules and hold promise in the treatment of both solid and hematologic malignancies. Herein, we discuss preclinical and clinical studies with this class of molecules.

Areas covered: In this review, we discuss the role of check point kinase 1 (CHK-1) in DNA repair and provide a comprehensive summary of pre-clinical and early phase clinical trials with CHK-1 inhibitors. We also provide molecular structural basis of CHK-1inhibitors binding to CHK-1.

Expert opinion: Available data from both pre-clinical and early clinical studies illustrates potential efficacy of this class of molecules when combined with antimetabolites in treating both solid and hematologic malignancies. In addition, there might be an additive role in combining this class of molecules to PARP inhibitors, platinum chemotherapy, or radiation therapy in p53 or BRCA mutated tumors. The safety of the aforementioned combination needs to be closely evaluated in the ongoing clinical trials.

KEYWORDS:

• CHK1
• inhibitors
• DNA
• cancer
• repair

Article highlights

• The check point kinase-1 (CHK-1) pathway holds a major role in in both SS and DS DNA repair.

• CHK-1 is involved in the global response to DNA damage through regulation of cell cycle and homologous DNA repair.

• CHK-1 inhibitors illustrated efficacy in early clinical trials when combined with other chemotherapies.

• There is a potential role in combining CHK-1 inhibitors with antimetabolites, PARP inhibitors, immune checkpoint inhibitors, or platinum chemotherapy.

• The safety profile of CHK-1 when combined with other chemotherapies needs to be monitored.

This box summarizes key points contained in the article.

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.

Additional information

Funding

This paper is not funded