4H58

BRAF in complex with compound 3

Summary for 4H58

• Entry DOI: 10.2210/pdb4h58/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, N-(4-{[(2-methoxyethyl)amino]methyl}phenyl)-6-(pyridin-4-yl)quinazolin-2-amine, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: protein kinase, structure based drug discovery, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : P15056
• Total number of polymer chains: 3
• Total formula weight: 94474.90

Authors

Vasbinder, M.,Aquila, B.,Augustin, M.,Chueng, T.,Cook, D.,Drew, L.,Fauber, B.,Glossop, S.,Godin, R.,Grondine, M.,Hennessy, E.,Johannes, J.,Lee, S.,Lyne, P.,Moertl, M.,Omer, C.,Palakurthi, S.,Pontz, T.,Read, J.,Sha, L.,Shen, M.,Steinbacher, S.,Wang, H.,Wu, A.,Ye, M.,Bagal, B. (deposition date: 2012-09-18, release date: 2013-02-27, Last modification date: 2023-09-20)

Primary citation

Vasbinder, M.M.,Aquila, B.,Augustin, M.,Chen, H.,Cheung, T.,Cook, D.,Drew, L.,Fauber, B.P.,Glossop, S.,Grondine, M.,Hennessy, E.,Johannes, J.,Lee, S.,Lyne, P.,Mortl, M.,Omer, C.,Palakurthi, S.,Pontz, T.,Read, J.,Sha, L.,Shen, M.,Steinbacher, S.,Wang, H.,Wu, A.,Ye, M.
Discovery and Optimization of a Novel Series of Potent Mutant B-Raf(V600E) Selective Kinase Inhibitors.
J.Med.Chem., 56:1996-2015, 2013

PubMed Abstract: B-Raf represents an attractive target for anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-Raf(V600E) kinase activity both in vitro and in vivo. Investigations into the structure-activity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-Raf(V600E) in vitro and showed preferential antiproliferative activity in mutant B-Raf(V600E) cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-Raf(V600E) A375 xenograft in vivo at a well-tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in nonmutant B-Raf cell lines in vitro.

PubMed: 23398453
DOI: 10.1021/jm301658d

Experimental method

X-RAY DIFFRACTION (3.1 Å)