Isawi Israa H, Obeidat Rayan M, Alnabulsi Soraya, Al Zoubi Rufaida
Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan.
Int J Mol Sci. 2025 May 4;26(9):4366. doi: 10.3390/ijms26094366.
Hematopoietic progenitor kinase 1 (HPK1), a negative regulator of T-cells, B-cells, and dendritic cells, has gained attention in antitumor immunotherapy research over the past decade. No HPK1 inhibitor has yet reached clinical approval, largely due to selectivity and drug-like limitations. Leveraging the available structural insights into HPK1, we conducted a rational hit identification using a structure-based virtual screening of over 600,000 drug-like molecules from ASINEX and OTAVA databases. A series of molecular docking studies, in vitro kinase assays, and molecular dynamics simulations were conducted to identify viable HPK1 inhibitor hits. This approach resulted in two promising novel hit scaffolds, 4H-Pyrido[1,2-a] thieno[2,3-d] pyrimidin-4-one (ISR-05) and quinolin-2(1H)-one (ISR-03), neither of which has previously been reported as an HPK1 inhibitor. ISR-05 and ISR-03 exhibited IC values of 24.2 ± 5.07 and 43.9 ± 0.134 µM, respectively, in kinase inhibition assays. These hits constitute tractable starting points for future hit-to-lead optimization aimed at developing more effective HPK1 inhibitors for cancer therapy.
造血祖细胞激酶1（HPK1）是T细胞、B细胞和树突状细胞的负调节因子，在过去十年的抗肿瘤免疫治疗研究中受到了关注。目前尚无HPK1抑制剂获得临床批准，这主要是由于选择性和类药性质方面的限制。利用现有的HPK1结构信息，我们通过对来自ASINEX和OTAVA数据库的60多万个类药分子进行基于结构的虚拟筛选，进行了合理的活性分子鉴定。开展了一系列分子对接研究、体外激酶测定和分子动力学模拟，以确定可行的HPK1抑制剂活性分子。这种方法产生了两个有前景的新型活性分子骨架，即4H-吡啶并[1,2-a]噻吩并[2,3-d]嘧啶-4-酮（ISR-05）和喹啉-2(1H)-酮（ISR-03），此前均未作为HPK1抑制剂报道过。在激酶抑制试验中，ISR-05和ISR-03的IC值分别为24.2±5.07和43.9±0.134µM。这些活性分子为未来旨在开发更有效的用于癌症治疗的HPK1抑制剂的活性分子到先导物优化提供了易于处理的起点。
