Sheng Jin, Chen Hong, Fu Bang, Pan Hongming, Wang Jiabing, Han Weidong
Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Betta Pharmaceuticals Co. Ltd., Hangzhou, Zhejiang, China.
NPJ Precis Oncol. 2024 Sep 11;8(1):198. doi: 10.1038/s41698-024-00686-8.
Aberrant activation of tropomyosin receptor kinases (TRKs) is a well-defined oncogenic driver for neurotrophic tropomyosin receptor kinase (NTRK)-fusion cancers, and acquired resistant mutations have emerged with clinical use of the first-generation TRK inhibitors. Here we present BPI-28592, a novel second-generation TRK inhibitor with efficacy against TRK fusion-positive cancers, including those with resistant mutations. Docking simulations indicated no steric hindrance between BPI-28592 and TRK mutants, suggesting its potential to overcome drug resistance. Biochemical assays showed strong inhibition and high selectivity against TRKA, TRKB, and TRKC. The inhibitor significantly reduced cell proliferation and blocked TRK signaling. In vivo studies demonstrated effective tumor suppression in xenograft models harboring TRK fusions with or without resistant mutations. Clinically, BPI-28592 achieved a complete response in a patient with malignant melanoma carrying an AP3S2-NTRK3 fusion (Clinicaltrials. gov identifier: NCT05302843).
原肌球蛋白受体激酶（TRKs）的异常激活是神经营养性原肌球蛋白受体激酶（NTRK）融合癌明确的致癌驱动因素，并且随着第一代TRK抑制剂的临床应用，已出现获得性耐药突变。在此，我们介绍BPI-28592，一种新型第二代TRK抑制剂，对TRK融合阳性癌症有效，包括那些具有耐药突变的癌症。对接模拟表明BPI-28592与TRK突变体之间不存在空间位阻，表明其具有克服耐药性的潜力。生化分析显示对TRKA、TRKB和TRKC具有强烈抑制作用和高选择性。该抑制剂显著降低细胞增殖并阻断TRK信号传导。体内研究表明，在携带或不携带耐药突变的TRK融合异种移植模型中，BPI-28592能有效抑制肿瘤。在临床上，BPI-28592在一名携带AP3S2-NTRK3融合的恶性黑色素瘤患者中实现了完全缓解（Clinicaltrials.gov标识符：NCT05302843）。
