4G9R

B-Raf V600E Kinase Domain Bound to a Type II Dihydroquinazoline Inhibitor

Summary for 4G9R

• Entry DOI: 10.2210/pdb4g9r/pdb
• Related: 4G9C
• Descriptor: Serine/threonine-protein kinase B-raf, 3-(2-cyanopropan-2-yl)-N-{4-methyl-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]phenyl}benzamide (2 entities in total)
• Functional Keywords: inhibitor, type ii, transferase, kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): P15056
• Total number of polymer chains: 2
• Total formula weight: 71398.27

Authors

Voegtli, W.C.,Sturgis, H.L. (deposition date: 2012-07-24, release date: 2012-11-14, Last modification date: 2024-02-28)

Primary citation

Wenglowsky, S.,Moreno, D.,Laird, E.R.,Gloor, S.L.,Ren, L.,Risom, T.,Rudolph, J.,Sturgis, H.L.,Voegtli, W.C.
Pyrazolopyridine inhibitors of B-Raf(V600E). Part 4: Rational design and kinase selectivity profile of cell potent type II inhibitors.
Bioorg.Med.Chem.Lett., 22:6237-6241, 2012

PubMed Abstract: Cell potent inhibitors of B-Raf(V600E) that bind to the kinase in the DFG-out conformation are reported. These compounds utilize the hinge-binding group and lipophilic linker from a previously disclosed series of B-Raf(V600E) inhibitors that bind to the kinase in an atypical DFG-in, αC-helix-out conformation. This new series demonstrates that DFG-out kinase inhibitors can be rationally designed from related inhibitors which utilize an unconventional binding mode. Kinase selectivity profiles are compared. The pattern of kinase selectivity was found to be determined by the feature of the inhibitor which extends into the back pocket of the kinase and leads to the kinase conformation, rather than by the hinge-binding group or other minor modifications.

PubMed: 22954737
DOI: 10.1016/j.bmcl.2012.08.007

Experimental method

X-RAY DIFFRACTION (3.2 Å)