Current strategies for targeting HPK1 in cancer and the barriers to preclinical progress

ABSTRACT

Introduction

Hematopoietic progenitor kinase 1 (HPK1), a 97-kDa serine/threonine Ste20-related protein kinase, functions as an intracellular negative regulator, primarily in hematopoietic lineage cells, where it regulates T cells, B cells, dendritic cells, and other immune cells. Loss of HPK1 kinase activity results in exacerbated cytokine secretion, enhanced T cell signaling, improved viral clearance, and thus increased restraint of tumor growth. These findings highlight HPK1 as a promising target for immuno-oncology treatments, culminating in the advancement of candidate compounds targeting HPK1 to clinical trials by several biotech enterprises.

Areas covered

Through searching PubMed, Espacenet-patent search, and clinicaltrials.gov, this review provides a comprehensive analysis of HPK1, encompassing its structure and roles in various downstream signaling pathways, the consequences of constitutive activation of HPK1, and potential therapeutic strategies to treat HPK1-driven malignancies. Moreover, the review outlines the patents issued for small molecule inhibitors and clinical investigations of HPK1.

Expert opinion

To enhance the success of tumor immunotherapy in clinical trials, it is important to develop protein degraders, allosteric inhibitors, and antibody-drug conjugates based on the crystal structure of HPK1, and to explore combination therapy approaches. Although several challenges remain, the development of HPK1 inhibitors display promising in preclinical and clinical studies.

KEYWORDS:

• Hematopoietic progenitor kinase 1 (HPK1)
• cancer immunotherapy
• cell signaling
• small molecule inhibitor
• clinical trial

Article highlights

• HPK1, an intracellular negative regulator, has been identified as a promising target for novel immuno-oncology drug development.

• HPK1 plays an important role in many downstream signaling pathways as a negative feedback regulator of cellular signaling.

• The many reported crystal structures of HPK1 provide guidance for the development of small molecule inhibitors. The patents issued for HPK1 inhibitors are listed.

• Therapeutics targeting HPK1 that are currently in preclinical studies and ongoing clinical trials exhibit significant potential as cancer immunotherapy and anti-infection treatments.

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.

Acknowledgments

We greatly thank Dr. Xingsen Wu at Tsinghua University for helpful discussion and useful suggestions. We also greatly thank Dr. Bei Zhang at Nanjing University of Information Science and Technology for her suggestions and support.

Additional information

Funding

This paper was funded by the China Postdoctoral Science Foundation [BX20220163] [2023M732005] and Postdoctoral Foundation of Tsinghua-Peking Center for Life Science.