9BFB

Crystal structure of BRAF kinase domain with PF-07284890

これはPDB形式変換不可エントリーです。

9BFB の概要

• エントリーDOI: 10.2210/pdb9bfb/pdb
• 分子名称: Serine/threonine-protein kinase B-raf, DI(HYDROXYETHYL)ETHER, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: braf inhibitor, kinase domain, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33855.47

構造登録者

Mou, T.-C. (登録日: 2024-04-17, 公開日: 2024-08-14)

主引用文献

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

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: 39077892
DOI: 10.1021/acs.jmedchem.4c00998

実験手法

X-RAY DIFFRACTION (1.92 Å)