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Discovery of macrocyclic derivatives bearing N-sulfonyl-pyrazole moiety as new potent hematopoietic progenitor kinase 1 inhibitors.

Li Wang,Zi-Long Li,Cheng-Xiang Duan,Xiu-Qin Yang,Hai-tong Wang,Xuanyu Gu,Guo-qiang Wang,Qian-Hui Cheng,Ming-Shu Wang,Neng-Fang She,Xing-Xing Shi,Wei Huang

Published 2025 in Bioorganic chemistry (Print)

ABSTRACT

Hematopoietic progenitor kinase 1 (HPK1), due to its crucial intracellular negative regulation of T-cell receptor (TCR) signaling, has emerged as a promising target of antitumor immunotherapy. Macrocyclization is an effective strategy to address the major challenges faced in the development of HPK1 inhibitors, as it can balance inhibitory efficacy, kinase selectivity, and pharmacokinetic properties. Herein, we continued this strategy and report a series of N-sulfonyl-pyrazole macrocyclic HPK1 inhibitors. Compound 14 exhibited excellent HPK1 inhibition with an IC50 value of 1.7 nM, as well as significant selectivity against GLK and LCK, which was confirmed in our molecular modeling studies to be caused by the interactions of cyclopropyl-sulfonyl group with different residues in the kinase domain. Compound 14 also displayed favorable human liver microsomal stability (T1/2 = 147.3 min) and considerable oral bioavailability (F = 22.8 %) in mice. More importantly, compound 14 demonstrated an additive synergistic effect with anti-PD-1 in a MC38 syngeneic tumor mouse model with a TGI% value of 89 % which was exhibited more pronouncedly in further subgroup analysis. These results indicated that compound 14 provided a perspective vision when used in combination of anti-PD-1 antibody as a new treatment regimen for patients who have insufficient response to current immunotherapy.

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