The HPK1 Inhibitor A‑745 Verifies the Potential of Modulating T Cell Kinase Signaling for Immunotherapy

Hematopoietic
progenitor kinase 1 (HPK1) is an MAP4K family member
within the Ste20-like serine/threonine branch of the kinome. HPK1
expression is limited to hematopoietic cells and has a predominant
role as a negative regulator of T cell function. Because of the central/dominant
role in negatively regulating T cell function, HPK1 has long been
in the center of interest as a potential pharmacological target for
immune therapy. The development of a small molecule HPK1 inhibitor
remains challenging because of the need for high specificity relative
to other kinases, including additional MAP4K family members, that
are required for efficient immune cell activation. Here, we report
the identification of the selective and potent HPK1 chemical probe,
A-745. In unbiased cellular kinase-binding assays, A-745 demonstrates
an excellent cellular selectivity binding profile within pharmacologically
relevant concentrations. This HPK1 selectivity translates to an in vitro immune cell activation phenotype reminiscent of
Hpk1-deficient and Hpk1-kinase-dead T cells, including augmented proliferation
and cytokine production. The results from this work give a path forward
for further developmental efforts to generate additional selective
and potent small molecule HPK1 inhibitors with the pharmacological
properties for immunotherapy.