Author: Shih, Pei-Yu ; Aliper, Alex ; Meng, Qingyuan ; Zhang, Man ; Ding, Xiaoyu ; Peng, Jingjing ; Ding, Xiao ; Lu, Hongfu ; Zhavoronkov, Alex ; Ren, Feng

Although immune checkpoint inhibitors (ICIs) have been a revelation for treating several cancers, an unmet need remains to broaden ICI therapeutic scope and increase their response rates in clinical trials. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T cell activation and has previously been identified as a promising target for immunotherapy. Herein, we report the discovery of a series of HPK1 inhibitors with novel 1(2H)-phthalazinone and 1(2H)-isoquinolinone scaffolds. Among them, compound 24 demonstrated potent in vitro activity (HPK1 IC₅₀ value of 10.4 nM) and cellular activity (pSLP76 EC₅₀ = 41 nM & IL-2 EC₅₀ = 108 nM). Compound 24 exhibited favorable mouse and rat pharmacokinetic profiles with reasonable oral exposure. Compound 24 showed potent in vivo anti-tumor activity in a CT26 syngeneic tumor model with 95 % tumor growth inhibition in combination with anti-PD-1.

01 Dec 2024·Bioorganic Chemistry

Design, synthesis, and biological evaluation of novel HPK1 inhibitors possessing 3-cyano-quinoline moiety

Article

Author: He, Chen ; Chen, Long ; Zhang, Baixue ; Duan, Yiping ; Zhong, Wenyi ; Xu, Jinyi ; Xu, Shengtao ; Yao, Hong ; Chen, Jichao ; Zhou, Pijun ; Wang, Tianyi

Hematopoietic progenitor kinase 1 (HPK1), a negative regulator of T cell receptor signaling, plays a crucial role in multiple cellular immune responses. Emerging researches have demonstrated that inhibiting HPK1 kinase function enhances T cells' ability to recognize tumor antigens and boosts anti-tumor immune responses. As a result, HPK1 has become a promising target for tumor immunotherapy. Herein, we report the design, synthesis, and biological evaluation of a series of novel HPK1 inhibitors featuring a 3-cyano-quinoline scaffold. Among these, compound 3a was identified as the most potent HPK1 inhibitor (HPK1 IC₅₀ = 48 nM). It effectively inhibited SLP76 phosphorylation, enhanced IL-2 cytokine secretion, and reversed PGE2-induced immunosuppression in Jurkat cells. In addition, compound 3a exhibited favorable metabolic stability in mouse liver microsomes and plasma. Overall, this work provides a structurally novel lead compound for the development of HPK1 inhibitors.

12 Sep 2024·ACS Medicinal Chemistry Letters

Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1

Article

Author: Mendonca, Rohan ; Wang, Weiru ; Wu, Ping ; Lainchbury, Michael ; Tellis, John C. ; Ran, Yinqing ; Wei, BinQing ; Kiefer, James ; Linehan, Jonathan L. ; Sneeringer, Chris ; An, Le ; Du, Xiangnan ; Pang, Jodie ; Kakiuchi-Kiyota, Satoko ; Luo, Xifeng ; Malhotra, Sushant ; Seward, Eileen ; Hu, Baihua ; Moffat, John G. ; Sethuraman, Vijay ; Heffron, Timothy P. ; Gazzard, Lewis ; Su, Dian ; Choo, Edna F. ; Chan, Bryan K. ; Chan, Grace Kayan ; Chen, Yong ; Siu, Michael

Hematopoietic progenitor kinase 1 (HPK1) serves a key immunosuppressive role as a negative regulator of T-cell receptor (TCR) signaling. HPK1 loss-of-function is associated with augmentation of immune function and has demonstrated synergy with immune checkpoint inhibitors in syngeneic mouse cancer models. These data offer compelling evidence for the use of selective small molecule inhibitors of HPK1 in cancer immunotherapy. We identified a novel series of isoquinoline HPK1 inhibitors through fragment-based screening that displayed promising levels of biochemical potency and activity in functional cell-based assays. We used structure-based drug design to introduce key selectivity elements while simultaneously addressing pharmacokinetic liabilities. These efforts culminated in a molecule demonstrating subnanomolar biochemical inhibition of HPK1 and strong in vitro augmentation of TCR signaling in primary human T-cells. Further profiling of this molecule revealed excellent kinase selectivity (347/356 kinases <50% inhibition @ 0.1 μM), a favorable in vitro safety profile, and good projected human pharmacokinetics.

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