Inhibitors of immuno-oncology target HPK1 – a patent review (2016 to 2020)

ABSTRACT

Introduction: Hematopoietic progenitor kinase (HPK1), a serine/threonine kinase, which is primarily expressed in hematopoietic cells is a negative regulator of T-cell receptor and B cell signaling. Studies using genetic disruption of HPK1 function show enhanced T-cell signaling, cytokine production, and in vivo tumor growth inhibition. This profile of enhanced immune response highlights small molecule inhibition of HPK1 as an attractive approach for the immunotherapy of cancer.

Areas covered: This article summarizes the biological rationale for the inhibition of HPK1 as a potential adjunct to the current immuno-oncology (IO) therapies. The article primarily discloses the current state of development of HPK1 inhibitors.

Expert Opinion: The rapid increase in the identification of small molecule inhibitors of HPK1 should translate into a fuller understanding of the role of HPK1 inhibition in the IO setting. This understanding will be of huge importance in determining whether HPK1 inhibition alone will be sufficient for tumor growth inhibition or if combination with current IO therapies will be required.

KEYWORDS:

• Kinase selectivity
• immuno-oncology
• HPK1
• MAP4K
• small-molecule inhibitors
• T-cell signaling

Article Highlights

1. HPK1 is a new target for human IO therapy 2. A number of small molecule HPK1 inhibitors have been identified 3. A range of hinge binding motifs disclosed 4. A consensus approach for targeting the P-loop identified 5. The kinome selectivity of these inhibitors will be key in understanding their role in the immunotherapy of cancer

Declaration of interest

I Linney was an employee of Charles River and is now an employee of C4X Discovery. N Kaila is an employee of Nimbus Therapeutics. The authors have 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

This paper was not funded.