29MASummary for 29MA
| Entry DOI | 10.2210/pdb29ma/pdb |
| Descriptor | Isoform 2B of GTPase KRas, PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | gtpase, nucleotide-binding protein, signal transduction, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 45446.66 |
| Authors | |
| Primary citation | Pozo, J.D.,Hennessy, E.,Schoepf, P.,Shibata, K.,Akemoto, K.,Abe, N.,Agnew, C.,Asakura, H.,Bennett, D.J.,Burgess, S.A.,Chai, X.,Chessari, G.,Day, P.J.,Duggal, R.,Giambasu, G.M.,Hamlett, C.C.F.,Jiang, Y.,Kida, T.,Komori, T.,Kondo, H.,Lacey, B.M.,Mayhood, T.W.,Miura, R.,Mizuarai, S.,Munsell, E.V.,O'Reilly, M.,Rath, B.,Rees, D.C.,Ryan, M.C.,Sagara, T.,Sakamoto, T.,De Jesus Silva, J.,Solban, N.,Song, X.S.,Sugimoto, T.,Terasaka, M.,Twigg, D.G.,Ueno, H.,Wakayama, K.,Xu, Z.,Yamamoto, T.,Stoeck, A.,Han, Y. Discovery of Novel Oral Covalent Inhibitors Targeting Active GTP-Bound KRASG12C with Potent Antitumor Activity. J.Med.Chem., 69:22187-22207, 2026 Cited by PubMed Abstract: Current KRASG12C inhibitors mainly target the inactive GDP-bound state, but clinical efficacy is limited, and resistance mechanisms have been identified. We disclose novel covalent inhibitors that selectively target the active GTP-bound KRASG12C. Starting from a high-throughput screen, we identified a keto-indolizine scaffold featuring an aniline-derived acrylamide warhead that covalently binds Cys12 in the switch-II pocket of active KRASG12C. X-ray crystallography revealed key interactions of acrylamide with GMPPCP's γ-phosphate, stabilizing the GTP state. We present medicinal chemistry efforts leading to the discovery of compound 17, which shows favorable oral bioavailability in preclinical species, exhibiting prolonged disruption of the KRAS-cRAF interaction and downstream ERK phosphorylation in vivo. In a KRASG12C-driven pancreatic cancer xenograft model (MIA PaCa-2), orally administered compound 17 achieved complete tumor regression for up to 45 days with good tolerability. This study establishes a novel class of KRASG12C inhibitors targeting the active GTP-bound state, which may have the potential to overcome some resistance mechanisms. PubMed: 42917916DOI: 10.1021/acs.jmedchem.6c01318 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.56 Å) |
Structure validation
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