Details

Autor(en) / Beteiligte

• Kettle, Jason G
• Bagal, Sharan K
• Bickerton, Sue
• Bodnarchuk, Michael S
• Boyd, Scott
• Breed, Jason
• Carbajo, Rodrigo J
• Cassar, Doyle J
• Chakraborty, Atanu
• Cosulich, Sabina
• Cumming, Iain
• Davies, Michael
• Davies, Nichola L
• Eatherton, Andrew
• Evans, Laura
• Feron, Lyman
• Fillery, Shaun
• Gleave, Emma S
• Goldberg, Frederick W
• Hanson, Lyndsey
• Harlfinger, Stephanie
• Howard, Martin
• Howells, Rachel
• Jackson, Anne
• Kemmitt, Paul
• Lamont, Gillian
• Lamont, Scott
• Lewis, Hilary J
• Liu, Libin
• Niedbala, Michael J
• Phillips, Christopher
• Polanski, Radek
• Raubo, Piotr
• Robb, Graeme
• Robinson, David M
• Ross, Sarah
• Sanders, Matthew G
• Tonge, Michael
• Whiteley, Rebecca
• Wilkinson, Stephen
• Yang, Junsheng
• Zhang, Wenman

Titel

Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRAS G12C

Ist Teil von

• Journal of medicinal chemistry, 2022-05, Vol.65 (9), p.6940-6952

Ort / Verlag

United States

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of , AZD4625, a clinical development candidate for the treatment of KRAS positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRAS with an anticipated low clearance and high oral bioavailability profile in humans.