Kong Deyu, Zhao Jichen, Huang Daowei, Stashko Michael A, Yan Dan, Ding Ransheng, Guduru Shiva K R, Zhou Yubai, Kania Catherine E, Shelton Earp H, Frye Stephen V, Huelse Justus M, Kireev Dmitri, DeRyckere Deborah, Graham Douglas K, Wang Xiaodong
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia 30322, United States.
J Med Chem. 2025 Apr 24;68(8):8455-8470. doi: 10.1021/acs.jmedchem.5c00009. Epub 2025 Apr 11.
The TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases has roles in oncogenesis and innate immunity, but the relative importance of the family members can differ in different contexts and between tumor types or individual tumors. Dual TYRO3 and MERTK inhibition may be advantageous for treatment of diseases or in tumors that are dependent on their coordinated action. Here, we report the discovery of the first potent dual TYRO3/MERTK inhibitor, UNC9435 (). UNC9435 has 46-fold and 120-fold selectivity of MERTK over AXL and FLT3, respectively, and selectively against a panel of 30 other kinases. TYRO3 and MERTK inhibitory activities were confirmed by NanoBRET assays in HEK293 cells, with <0.51 nM EC values for both enzymes and >3000-fold selectivity over AXL. UNC9435 also inhibited TYRO3, MERTK, and downstream oncogenic signaling in cancer cells and reduced colony formation in non-small cell lung cancer cultures, indicating its potential as a novel cancer therapeutic.
受体酪氨酸激酶TAM（TYRO3、AXL、MERTK）家族在肿瘤发生和先天免疫中发挥作用，但家族成员的相对重要性在不同背景以及不同肿瘤类型或个体肿瘤之间可能有所不同。双重抑制TYRO3和MERTK对于治疗依赖其协同作用的疾病或肿瘤可能具有优势。在此，我们报告了首个强效双重TYRO3/MERTK抑制剂UNC9435（）的发现。UNC9435对MERTK的选择性分别比对AXL和FLT3高46倍和120倍，并且对其他30种激酶具有选择性。在HEK293细胞中通过纳米生物发光共振能量转移（NanoBRET）分析证实了TYRO3和MERTK的抑制活性，两种酶的半数有效浓度（EC）值均<0.51 nM，对AXL的选择性>3000倍。UNC9435还抑制癌细胞中的TYRO3、MERTK和下游致癌信号传导，并减少非小细胞肺癌培养物中的集落形成，表明其作为新型癌症治疗药物的潜力。
