Monday, March 28, 2022

Discovery of SPH5030, a Selective, Potent, and Irreversible Tyrosine Kinase Inhibitor for HER2-Amplified and HER2-Mutant Cancer Treatment

Di Li, Yuanxiang Tu, Kaijun Jin, Lingjun Duan, Yuan Hong, Jia Xu, Na Chen, Zhihui Zhang, Hongjian Zuo, Wanchun Gong, Jing Zhang, Qian Wang, Hai Qian, Xuenan Wang, Ying Ke, and Guangxin Xia
Journal of Medicinal Chemistry 2022

DOI: 10.1021/acs.jmedchem.1c00710

Small-molecule irreversible tyrosine kinase inhibitors as high potent agents have led to improvements in disease-free and overall survival in patients with HER2-amplified cancer. The approved irreversible HER2 inhibitors, neratinib and pyrotinib, both lack HER2 selectivity, leading to off-target adverse events in patients. The development of HER2 mutation during treatment also hampers the progress of the treatment. We used a molecular hybridization strategy for structural optimizations, in conjunction with in vitro and in vivo drug-like property screening, to obtain a clinical candidate SPH5030. Overall, SPH5030 showed excellent activities against four frequent kinds of HER2 mutants and high relative HER2 selectivity compared with neratinib and pyrotinib, good pharmacokinetic characteristics with desirable bioavailabilities, and significant in vivo antitumor efficacy in xenograft mouse models, especially in a HER2 mutation A775_G776insYVMA xenograft mouse model with its potency much higher than those of neratinib and pyrotinib.

Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry

Roman C. Sarott, Inchul You, Yen-Der Li, Sean T. Toenjes, Katherine A. Donovan, Pooreum Seo, Martha Ordonez, Woong Sub Byun, Muhammad Murtaz...