6N2K

Tetrahydropyridopyrimidines as Covalent Inhibitors of KRAS-G12C

Summary for 6N2K

• Entry DOI: 10.2210/pdb6n2k/pdb
• Related: 6N2J
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: kras proto-oncogene, gtpase, oncoprotein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 20338.94

Authors

Vigers, G.P. (deposition date: 2018-11-13, release date: 2018-12-12, Last modification date: 2024-11-20)

Primary citation

Fell, J.B.,Fischer, J.P.,Baer, B.R.,Ballard, J.,Blake, J.F.,Bouhana, K.,Brandhuber, B.J.,Briere, D.M.,Burgess, L.E.,Burkard, M.R.,Chiang, H.,Chicarelli, M.J.,Davidson, K.,Gaudino, J.J.,Hallin, J.,Hanson, L.,Hee, K.,Hicken, E.J.,Hinklin, R.J.,Marx, M.A.,Mejia, M.J.,Olson, P.,Savechenkov, P.,Sudhakar, N.,Tang, T.P.,Vigers, G.P.,Zecca, H.,Christensen, J.G.
Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity.
ACS Med Chem Lett, 9:1230-1234, 2018

PubMed Abstract: 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 will be highlighted.

PubMed: 30613331
DOI: 10.1021/acsmedchemlett.8b00382

Experimental method

X-RAY DIFFRACTION (1.72 Å)