8V8H
PI3Ka H1047R co-crystal structure with inhibitor in cryptic pocket near H1047R (compound 4).
Summary for 8V8H
| Entry DOI | 10.2210/pdb8v8h/pdb |
| Related | 8V8I 8V8J 8V8U 8V8V |
| Descriptor | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 2-({(1R)-1-[2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-4H-1-benzopyran-8-yl]ethyl}amino)benzoic acid, ... (4 entities in total) |
| Functional Keywords | h1047r, pi3k, pi3ka, signaling protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 318638.93 |
| Authors | Gunn, R.J.,Lawson, J.D. (deposition date: 2023-12-05, release date: 2024-03-20, Last modification date: 2024-04-10) |
| Primary citation | Ketcham, J.M.,Harwood, S.J.,Aranda, R.,Aloiau, A.N.,Bobek, B.M.,Briere, D.M.,Burns, A.C.,Caddell Haatveit, K.,Calinisan, A.,Clarine, J.,Elliott, A.,Engstrom, L.D.,Gunn, R.J.,Ivetac, A.,Jones, B.,Kuehler, J.,Lawson, J.D.,Nguyen, N.,Parker, C.,Pearson, K.E.,Rahbaek, L.,Saechao, B.,Wang, X.,Waters, A.,Waters, L.,Watkins, A.H.,Olson, P.,Smith, C.R.,Christensen, J.G.,Marx, M.A. Discovery of Pyridopyrimidinones that Selectively Inhibit the H1047R PI3K alpha Mutant Protein. J.Med.Chem., 67:4936-4949, 2024 Cited by PubMed Abstract: The H1047R mutation of is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3Kα over PI3Kα is crucial due to the role that PI3Kα plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3Kα-selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3Kα with high selectivity over PI3Kα, resulting in the discovery of compound . When dosed in the HCC1954 tumor model in mice, provided tumor regressions and a clear pharmacodynamic response. X-ray cocrystal structures from several PI3Kα inhibitors were obtained, revealing three distinct binding modes within PI3Kα including a previously reported cryptic pocket in the C-terminus of the kinase domain wherein we observe a ligand-induced interaction with Arg1047. PubMed: 38477582DOI: 10.1021/acs.jmedchem.4c00078 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.58 Å) |
Structure validation
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