Sherry Niessen, Melissa M.Dix, Sabrina Barbas, Zachary Potter. Shuyan Lu, Oleg Brodsky, Simon Planken, Douglas Behenna, Chau Almaden, Ketan S. Gajiwala, Kevin Ryan, Rose Ann Ferre, Michael R. Lazear. Matthew M.Hayward, John C. Kath, Benjamin F. Cravatt
Cell Chemical Biology, 2017
Patients with non-small cell lung cancers that have kinase-activating epidermal growth factor receptor (EGFR) mutations are highly responsive to first- and second-generation EGFR inhibitors. However, these patients often relapse due to a secondary, drug-resistant mutation in EGFR whereby the gatekeeper threonine is converted to methionine (T790M). Several third-generation EGFR inhibitors have been developed that irreversibly inactivate T790M-EGFR while sparing wild-type EGFR, thus reducing epithelium-based toxicities. Using chemical proteomics, we show here that individual T790M-EGFR inhibitors exhibit strikingly distinct off-target profiles in human cells. The FDA-approved drug osimertinib (AZD9291), in particular, was found to covalently modify cathepsins in cell and animal models, which correlated with lysosomal accumulation of the drug. Our findings thus show how chemical proteomics can be used to differentiate covalent kinase inhibitors based on global selectivity profiles in living systems and identify specific off-targets of these inhibitors that may affect drug activity and safety.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter and @email@example.com on Mastodon
Sunday, October 8, 2017
Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors
Covalent drug discovery using sulfur(VI) fluoride exchange warheads
Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 https://doi.org/10.1080/17460441.2023.2218642 Covalent drug discovery has ...
Zhao, Z.; Bourne, P. E. ChemRxiv 2022 . https://doi.org/10.26434/chemrxiv-2022-nlb0m Kinase-targeted drug discovery for cancer therapy ha...
Wang, S.; Hadisurya, M.; Tao, W. A.; Dykhuizen, E.; Krusemark, C. ChemRxiv 2022 . https://doi.org/10.26434/chemrxiv-2022-tvgn1 Targeted co...
Jian Ding, Guo Li, Hejun Liu, Lulu Liu, Ying Lin, Jingyan Gao, Guoqiang Zhou, Lingling Shen, Mengxi Zhao, Yanyan Yu, Weihui Guo, Ulrich Homm...