MedChemCASES is a new online seminar series of the GDCh Division of Medicinal Chemistry, presenting exciting medicinal chemistry case studies from industry and academia. The program is designed together with the new dynamic NextGenMedChem group.
Dr. Doyle Cassar (Astra-Zeneca)
July 9, 2020
4:00 p.m. (Berlin time)
The seminar is free of charge, but REGISTRATION is needed.
“Allosteric Covalent Inhibitors of the Mutant GTPase KRASG12C”
Of all human cancers, 20% have a mutation in GTPase KRAS with a high frequency being found in pancreatic, colorectal and non-small cell lung cancer (NSCLC). A glycine to cysteine mutation at codon 12 is the most frequent mutation found in NSCLC, rendering KRAS constitutively active and driving cell proliferation, survival and differentiation. Covalent targeting of this cysteine residue offers the potential for selective inhibitors of the G12C mutant isoform and an allosteric mode of action potentially negates the impact of high nucleotide binding affinity for the GTPase. A knowledge- and structure-based design approach was utilised to derive diverse series of covalent inhibitors that interact directly with this cysteine mutation, causing a shift in the switch II region and rendering KRAS inactive. This talk will highlight our development of a series of candidates with excellent DMPK properties and superior efficacy to other agents targeting this mechanism.
zuletzt geändert am: 06.07.2020 10:08 Uhr von C.Kniep