9P46
Crystal structure of HRAS-G12D/Q95H (GMPPNP-bound) in complex with BBO-11818
This is a non-PDB format compatible entry.
Summary for 9P46
| Entry DOI | 10.2210/pdb9p46/pdb |
| Descriptor | GTPase HRas, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | hras, ras, h-ras, inhibitor, bbo-11818, bbo11818, bbo, theras, bridgebio, oncoprotein, oncoprotein-inhibitor complex |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 41327.99 |
| Authors | Chan, A.H.,Bratcher, D.R.,Simanshu, D.K. (deposition date: 2025-06-16, release date: 2025-12-03, Last modification date: 2026-03-18) |
| Primary citation | Stahlhut, C.,Maciag, A.E.,Sullivan, K.A.,Singh, K.,Gitego, N.,Zhang, Z.,Chan, A.H.,Sharma, A.K.,Alexander, P.A.,Shu, J.,Yang, Y.,Rigby, M.,Ma, R.,Setoodeh, S.,Smith, B.P.,Pei, J.,Rabara, D.,Larsen, E.K.,Turner, D.M.,Zhang, C.,Feng, C.,Feng, S.,Stice, J.P.,Xu, R.,Lin, K.,Stephen, A.G.,Lightstone, F.C.,Ji, C.,Wang, K.,Simanshu, D.K.,Nissley, D.V.,Wallace, E.,Wang, B.,Sinkevicius, K.W.,McCormick, F.,Beltran, P.J. Discovery of BBO-11818, a Potent and Selective Noncovalent Inhibitor of (ON) and (OFF) KRAS with Activity against Multiple Oncogenic Mutants. Cancer Discov, :OF1-OF20, 2026 Cited by PubMed Abstract: Although KRASG12C-specific inhibitors have been introduced, no approved targeted therapies exist for other clinically significant KRAS mutants, including KRASG12D and KRASG12V. We discovered BBO-11818, a potent, selective, orally bioavailable noncovalent pan-KRAS inhibitor capable of targeting multiple KRAS mutants in both the inactive GDP-bound (OFF) and active GTP-bound (ON) states. BBO-11818 binds in the Switch-II/Helix 3 pocket, inducing conformational changes incompatible with effector binding, and demonstrates high-affinity binding to mutant KRAS with strong selectivity over NRAS and HRAS. BBO-11818 potently inhibited MAPK signaling and cellular viability specifically in KRAS-driven lines and produced tumor regressions in KRAS-mutant xenograft models. Combination studies with anti-PD-1, anti-EGFR antibodies, and a RAS:PI3Kα breaker compound showed enhanced efficacy. BBO-11818 has entered phase I clinical trials for patients with various KRAS mutations in colorectal, pancreatic, and lung cancers (NCT06917079). PubMed: 41790032DOI: 10.1158/2159-8290.CD-25-1280 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.02 Å) |
Structure validation
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