Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity
| Autor: | Joshua Ballard, Harrah Chiang, James G. Christensen, Kenneth Hee, Tony Pisal Tang, Brian R. Baer, Peter Olson, Henry J. Zecca, David Briere, Mark Joseph Chicarelli, Laurence E. Burgess, Karyn Bouhana, Jill Hallin, Matthew A. Marx, Lauren Hanson, Barbara J. Brandhuber, Michael Burkard, Fell Jay Bradford, Pavel Savechenkov, James F. Blake, John P. Fischer, Guy Vigers, Hicken Erik James, Niranjan Sudhakar, Kevin Davidson, Ronald Jay Hinklin, Macedonio J. Mejia, John Gaudino |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
endocrine system diseases Oncogene Chemistry Organic Chemistry Cancer medicine.disease_cause medicine.disease Biochemistry Small molecule digestive system diseases respiratory tract diseases 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Covalent bond In vivo 030220 oncology & carcinogenesis Drug Discovery medicine Cancer research KRAS neoplasms Function (biology) Cysteine |
| Zdroj: | ACS Medicinal Chemistry Letters. 9:1230-1234 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.8b00382 |
| Popis: | [Image: see text] KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible. We have discovered a series of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. The PK/PD and efficacy of compound 13 will be highlighted. |
| Databáze: | OpenAIRE |
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