Thursday, October 7, 2021

Characterization of an Aromatic Trifluoromethyl Ketone as a New Warhead for Covalently Reversible Kinase Inhibitor Design

Zhen Zhang, Yongjin Wang, Xiaojuan Chen, Xiaojuan Song, Zhengchao Tu, Yongheng Chen, Zhimin Zhang, Ke Ding,

Bioorganic & Medicinal Chemistry,2021, 116457,

An aromatic trifluoromethyl ketone moiety was characterized as a new warhead for covalently reversible kinase inhibitor design to target the non-catalytic cysteine residue. Potent and selective covalently reversible inhibitors of FGFR4 kinase were successfully designed and synthesized by utilizing this new warhead. The binding mode of a representative inhibitor was fully characterized by using multiple technologies including MALDI-TOF mass spectrometry, dialysis assay and X-ray crystallographic studies etc. This functional group was also successfully applied to discovery of a new JAK3 inhibitor, suggesting its potential application in designing other kinase inhibitors.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...