Wu Kaifu, He Rui, Li Zongyang, Qiu Kongxi, Xiao Guorong, Peng Lijie, Meng Xiangbao, Zheng Canhui, Zhang Zhang, Cai Qian
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518035, China.
Eur J Med Chem. 2023 May 5;251:115237. doi: 10.1016/j.ejmech.2023.115237. Epub 2023 Mar 3.
Rearranged during transfection (RET) is a promising target for antitumor drug development. Multikinase inhibitors (MKI) have been developed for RET-driven cancers but displayed limited efficacy in disease control. Two selective RET inhibitors were approved by FDA in 2020 and proved potent clinical efficacy. However, the discovery of novel RET inhibitors with high target selectivity and improved safety is still highly desirable. Herein, we reported a class of 3,5-diaryl-1H-pyrazol-based ureas as new RET inhibitors. The representative compounds 17a/b displayed high selectivity to other kinases, and potently inhibited isogenic BaF3-CCDC6-RET cells harboring wild-type, or gatekeeper mutation (V804M). They also displayed moderate potency against BaF3-CCDC6-RET-G810C with solvent-front mutation. Compound 17b showed better pharmacokinetics properties and demonstrated promising oral in vivo antitumor efficacy in a BaF3-CCDC6-RET-V804M xenograft model. It may be utilized as a new lead compound for further development.
转染重排（RET）是抗肿瘤药物开发的一个有前景的靶点。多激酶抑制剂（MKI）已被开发用于RET驱动的癌症，但在疾病控制方面显示出有限的疗效。2020年，两种选择性RET抑制剂获得美国食品药品监督管理局（FDA）批准，并证明具有强大的临床疗效。然而，仍然非常需要发现具有高靶点选择性和更高安全性的新型RET抑制剂。在此，我们报道了一类基于3,5-二芳基-1H-吡唑的脲类作为新型RET抑制剂。代表性化合物17a/b对其他激酶具有高选择性，并能有效抑制携带野生型或守门人突变（V804M）的同基因BaF3-CCDC6-RET细胞。它们对具有溶剂前沿突变的BaF3-CCDC6-RET-G810C也显示出中等效力。化合物17b表现出更好的药代动力学性质，并在BaF3-CCDC6-RET-V804M异种移植模型中显示出有前景的口服体内抗肿瘤疗效。它可作为进一步开发的新先导化合物。
