4PP7

Highly Potent and Selective 3-N-methylquinazoline-4(3H)-one Based Inhibitors of B-RafV600E Kinase

Summary for 4PP7

• Entry DOI: 10.2210/pdb4pp7/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, N-{2,4-difluoro-3-[methyl(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]phenyl}propane-1-sulfonamide (2 entities in total)
• Functional Keywords: serine/threonine-protein kinase b-raf, 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: 71280.16

Authors

Wenglowsky, S.,Ren, L.,Grina, J.,Hansen, J.D.,Laird, E.R.,Moreno, D.,Dinkel, V.,Gloor, S.L.,Hastings, G.,Rana, S.,Rasor, K.,Sturgis, H.L.,Voegtli, W.C.,Vigers, G.P.A.,Willis, B.,Mathieu, S.,Rudolph, J. (deposition date: 2014-02-26, release date: 2014-04-09, Last modification date: 2024-02-28)

Primary citation

Wenglowsky, S.,Ren, L.,Grina, J.,Hansen, J.D.,Laird, E.R.,Moreno, D.,Dinkel, V.,Gloor, S.L.,Hastings, G.,Rana, S.,Rasor, K.,Sturgis, H.L.,Voegtli, W.C.,Vigers, G.,Willis, B.,Mathieu, S.,Rudolph, J.
Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-Raf(V600E) kinase.
Bioorg.Med.Chem.Lett., 24:1923-1927, 2014

PubMed Abstract: Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf inhibitor, a finding that should have broad application in kinase drug discovery.

PubMed: 24675381
DOI: 10.1016/j.bmcl.2014.03.007

Experimental method

X-RAY DIFFRACTION (3.4 Å)