9B4U
Crystal structure of p110alpha-RBD covalently bound to a breaker compound BBO-10203 via Cys242
This is a non-PDB format compatible entry.
Summary for 9B4U
| Entry DOI | 10.2210/pdb9b4u/pdb |
| Descriptor | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, 1-[(4R,8R)-2-[(4M,7P)-7-[2,4-difluoro-6-(2-methoxyethoxy)phenyl]-4-(1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl]-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]propan-1-one (3 entities in total) |
| Functional Keywords | p110alpha, pik3ca, pi3kalpha, rbd, breaker, pi3k-ras, 10203, oncoprotein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 34885.02 |
| Authors | |
| Primary citation | Simanshu, D.K.,Xu, R.,Stice, J.P.,Czyzyk, D.J.,Feng, S.,Denson, J.P.,Riegler, E.,Yang, Y.,Zhang, C.,Donovan, S.,Smith, B.P.,Abreu-Blanco, M.,Chen, M.,Feng, C.,Fu, L.,Rabara, D.,Young, L.C.,Dyba, M.,Yan, W.,Lin, K.,Ghorbanpoorvalukolaie, S.,Larsen, E.K.,Malik, W.,Champagne, A.,Parker, K.,Ju, J.H.,Jeknic, S.,Esposito, D.,Turner, D.M.,Lightstone, F.C.,Wang, B.,Wehn, P.M.,Wang, K.,Stephen, A.G.,Maciag, A.E.,Hata, A.N.,Sinkevicius, K.W.,Nissley, D.V.,Wallace, E.M.,McCormick, F.,Beltran, P.J. BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3K alpha interaction. Science, :eadq2004-eadq2004, 2025 Cited by PubMed Abstract: BBO-10203 is an orally available drug that covalently and specifically binds to the RAS-binding domain of phosphoinositide 3-kinase α (PI3Kα), preventing its activation by HRAS, NRAS, and KRAS. It inhibited PI3Kα activation in tumors with oncogenic mutations in or , and in tumors with human epidermal growth factor receptor 2 (HER2) amplification or overexpression. In preclinical models, BBO-10203 caused significant tumor growth inhibition across multiple tumor types and showed enhanced efficacy in combination with inhibitors of cyclin-dependent kinase 4/6 (CDK4/6), estrogen receptor (ER), HER2 and KRAS-G12C mutant, including in tumors harboring mutations in Kelch-like ECH-associated protein 1 (KEAP1) and Serine/Threonine Kinase 11 (STK11). Notably, these antitumor effects occurred without inducing hyperglycemia, as insulin signaling does not depend on RAS-mediated PI3Kα activation to promote glucose uptake. PubMed: 40504949DOI: 10.1126/science.adq2004 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.21 Å) |
Structure validation
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