Antibody-based immune checkpoint inhibitors remain a major focus of immuno-oncology drug research and development efforts because of their recent success in providing long-term anti-tumor responses. However, the range of response of different tumor types to these drugs is hugely varied. Small molecule kinase inhibitors that block signaling pathways involved in regulation of tumor immunity at multiple points in the “cancer immunity cycle” may provide alternate, effective therapeutics. One kinase that may be a target for such small molecule inhibitors is Hematopoietic Progenitor Kinase 1 or HPK1; the potential of this kinase as a therapeutic target was reviewed by Sawasdikosol and Burakoff (1). HPK1, also known as MAP4K1, is a member of the MAP kinase protein kinase family that negatively regulates signal transduction in T-cells, B-cells and dendritic cells of the immune system.
Wang, et al. recently showed that chemical inhibition of HPK1 using a small molecule inhibitor enhanced Th1 cytokine production in T-cells and restored immune suppression induced by prostaglandin E2 (PGE2) and adenosine pathways in human T-cells (2). In combination with the monoclonal antibody pembrolizumab, which binds PD-1, they demonstrate a synergistic effect resulting in increased interferon (IFN-γ) production (2).
The targeting of kinases such as HPK1 for cancer drug development has several advantages. First, it relies on approaches to drug discovery that have been tested and optimized for many years. Second efforts to identify small molecule inhibitors can take advantage of existing large libraries of small molecule compounds, and such libraries are amenable to high-throughput screening for candidate inhibitors. Any candidate molecules that do emerge can be improved through medicinal chemistry research to increase specificity, potency and other desirable characteristics using available bioinformatics and our current understanding of kinase structural domains.
HPK1 is an attractive kinase to target in a drug screen because it exercises multiple negative effects in almost every step of the cancer-immunity cycle. In addition to the roles such a kinase plays in the cancer-immunity cycle, genetic evidence that it plays a role in cancer progression is desirable. Such genetic evidence for HPK1 is available from mouse studies, but no mutations of HPK1 gene in humans have been directly linked to any human diseases (1). If the targeted kinase is also only expressed in immune cells, the occurrence of adverse effects caused by inhibiting the kinase in other tissues could be minimized.
HPK1 and other kinases with similar characteristics could well become an important tool in the immuno-oncology tool kit.
Are you interested in studying HPK1? The HPK1 Kinase Enzyme System includes HPK1 (human, recombinant; amino acids 1–346), myelin basic protein (MBP) Substrate, Reaction Buffer and DTT and is optimized for use with the ADP-Glo Kinase Assay.
Want to study intracellular binding of your lead compounds to HPK1 in live cells? The NanoLuc®-MAP4K1 Fusion Vector contains the coding region of NanoLuc® luciferase fused to the N-terminus of human MAP4K1 (HPK1) kinase. It is designed for use with the NanoBRET™ Target Engagement (TE) Intracellular Kinase Assay, where the plasmid can be transfected into various cell lines for MAP4K1 target engagement analysis.
- Sawasdikosol, S. and Steven Burakoff (2020) A perspective on HPK1 as a novel immuno-oncology drug target. DOI: 10.7554/eLife.55122
- Wang, Y, et al (2020) Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function. DOI: 10.1371/journal.pone.0243145