9BFB
Crystal structure of BRAF kinase domain with PF-07284890
This is a non-PDB format compatible entry.
Summary for 9BFB
| Entry DOI | 10.2210/pdb9bfb/pdb |
| Descriptor | Serine/threonine-protein kinase B-raf, DI(HYDROXYETHYL)ETHER, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | braf inhibitor, kinase domain, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 33855.47 |
| Authors | |
| Primary citation | Ren, L.,Moreno, D.,Baer, B.R.,Barbour, P.,Bettendorf, T.,Bouhana, K.,Brown, K.,Brown, S.A.,Fell, J.B.,Hartley, D.P.,Hicken, E.J.,Laird, E.R.,Lee, P.,McCown, J.,Otten, J.N.,Prigaro, B.,Wallace, R.,Kahn, D. Identification of the Clinical Candidate PF-07284890 ( ARRY-461 ), a Highly Potent and Brain Penetrant BRAF Inhibitor for the Treatment of Cancer. J.Med.Chem., 67:13019-13032, 2024 Cited by PubMed Abstract: Mutant BRAF is one of the most common oncogenic drivers in metastatic melanoma. While first generation BRAF inhibitors are capable of controlling tumors systemically, they are unable to adequately treat tumors that have metastasized to the brain due to insufficient penetration across the blood-brain barrier (BBB). Through a combination of structure-based drug design (SBDD) and the optimization of physiochemical properties to enhance BBB penetration, we herein report the discovery of the brain-penetrant BRAF inhibitor () In mice studies, proved to be highly brain-penetrant and was able to drive regressions of A375 BRAF tumors implanted both subcutaneously and intracranially. Based on compelling preclinical safety and efficacy studies, was progressed into a Phase 1 A/B clinical trial (NCT04543188). PubMed: 39077892DOI: 10.1021/acs.jmedchem.4c00998 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.92 Å) |
Structure validation
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