Tuesday, November 6, 2018

Neolymphostin A is a Covalent Phosphoinositide-3-kinase (PI3-K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor that Employs an Unusual Electrophilic Vinylogous Ester

Gabriel Castro-Falcón, Grant Seiler, Ozlem Demir, Manoj Rathinaswamy, David Hamelin, Reece M. Hoffmann, Stefanie Makowski, Anne-Catrin Letzel, Seth Field, John Burke, Rommie E. Amaro, and Chambers C. Hughes

Journal of Medicinal Chemistry 2018
DOI: 10.1021/acs.jmedchem.8b00975

Using a novel chemistry-based assay for identifying electrophilic natural products from unprocessed extracts, we identified the PI3-kinase/mTOR dual inhibitor neolymphostin A from Salinispora arenicola CNY-486. The method further showed that the vinylogous ester substituent on the neolymphostin core was the exact site for enzyme conjugation. Tandem MS/MS experiments on PI3Kα treated with the inhibitor revealed that neolymphostin covalently modified Lys802 with a shift in mass of +306 amu, corresponding to addition of the inhibitor and elimination of methanol. The binding pose of the inhibitor bound to PI3Kα was modelled, and hydrogen-deuterium exchange mass spectrometry experiments supported this model. Against a panel of kinases, neolymphostin showed good selectivity for PI3-kinase and mTOR. In addition, the natural product blocked AKT phosphorylation in live cells with an IC50 of ~3 nM. Taken together, neolymphostin is the first reported example of a covalent kinase inhibitor from the bacterial domain of life.

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...