From inhibition to degradation: advances in highly selective targeting strategies for HPK1.

Hematopoietic progenitor kinase 1 (HPK1) is a serine/threonine kinase specific to the hematopoietic system. As a member of the mammalian Ste20-related MAP4K kinase family, HPK1 serves as a key negative regulator of T cell-mediated immune responses. It is implicated in the development of human malignancies. Consequently, HPK1 has emerged as a highly promising target for cancer immunotherapy. Inhibition of HPK1 can abrogate its suppressive effects on T cell activation and function. However, HPK1 shares high structural homology with other MAP4K family members, particularly GLK. This poses a major challenge to the development of highly selective inhibitors. Achieving selectivity by distinguishing HPK1 from other family kinases and key T-cell activation kinases is crucial. It helps minimize off‑target side effects and broaden the therapeutic window. This review summarizes advances in HPK1-targeting strategies from 2016 to 2026. Focusing on the structural classes and selectivity optimization mechanisms of highly selective small-molecule HPK1 inhibitors, as well as breakthroughs in the development of proteolysis-targeting chimeras (PROTACs). The structural biology basis underlying HPK1 selectivity regulation is also analyzed. Finally, this review addresses the challenges in developing HPK1-targeted formulations and discusses future research directions, with the aim of providing a reliable reference for the rational design and clinical translation of novel, highly selective HPK1-targeted therapeutic strategies.