Investigational CHK1 inhibitors in early phase clinical trials for the treatment of cancer

ABSTRACT

Introduction: Checkpoint kinase 1 (CHK1) inhibitors have been in development for two decades. The initial CHK1 inhibitor staurosporine analog, UCN01, entered clinical trials whilst it was still considered to act via PKC inhibition; only later were trials performed in a more focused fashion to determine whether CHK1 inhibition could dysregulate cell cycle checkpoints. Many of the subsequently synthesized more specific CHK1 inhibitors have failed because of poor PK/PD or cumulative normal tissue toxicities in patients. CHK1 inhibitor monotherapy often demonstrates limited efficacy and in general, must be combined with other agents. The combination of CHK1 inhibitors with modern signaling regulators may be a better therapeutic strategy.

Areas covered: This review discusses the history of, and translational use of CHK1 inhibitors; the latest generation of CHK1 inhibitors to enter clinic development are also examined.

Expert opinion: Some CHK1 inhibitors can be administered safely, but that when they are combined with traditional cytotoxic DNA damaging agents, the normal tissue toxicities outweigh the very modest gains in therapeutic efficacy. Researchers need to think outside of the box and consider how CHK1 inhibitors can be combined with other signal transduction modulators such as MEK1/2 and PARP1 inhibitors to kill tumor cells.

KEYWORDS:

• CHK1
• DNA damage
• survival signaling

Article Highlights

• CHK1 kinase plays a key role in the management of DNA repair and replication and cell cycle progression in tumor cells.

• Some CHK1 inhibitors can be administered safely, but when they are combined with traditional cytotoxic DNA damaging agents, the normal tissue toxicities outweigh the very modest gains in therapeutic efficacy.

• No agent within this class of kinase inhibitors has reached phase III evaluation or FDA approval.

• Despite new encouraging data with the latest versions of CHK1 inhibitors, there is a major question mark over the efficacy in patients.

• Researchers need to think outside of the box and consider how CHK1 inhibitors can be combined with other signal transduction modulators such as MEK1/2 and PARP1 inhibitors to kill tumor cells.

This box summarizes key points contained in the article.

Declaration of interest

P Dent receives funding from Genzada Pharmaceuticals and Puma Pharmaceuticals. The author has no other 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.

Additional information

Funding

The work of the authors is supported by philanthropic funding from Massey Cancer Center and the Universal Inc. Chair in Signal Transduction Research, the Commonwealth Health Research Board (CHRB) of Virginia and The US National Cancer Institute (R01 CA192613),