7K0V

Crystal structure of bRaf in complex with inhibitor GNE-0749

Summary for 7K0V

• Entry DOI: 10.2210/pdb7k0v/pdb
• Descriptor: Non-specific serine/threonine protein kinase, N-(3,3-dimethylbutyl)-N'-{2-fluoro-5-[(5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]-4-methylphenyl}urea, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 133175.35

Authors

Yin, J.,Eigenbrot, C.E.,Wang, W. (deposition date: 2020-09-06, release date: 2021-05-26, Last modification date: 2023-10-18)

Primary citation

Huestis, M.P.,Dela Cruz, D.,DiPasquale, A.G.,Durk, M.R.,Eigenbrot, C.,Gibbons, P.,Gobbi, A.,Hunsaker, T.L.,La, H.,Leung, D.H.,Liu, W.,Malek, S.,Merchant, M.,Moffat, J.G.,Muli, C.S.,Orr, C.J.,Parr, B.T.,Shanahan, F.,Sneeringer, C.J.,Wang, W.,Yen, I.,Yin, J.,Siu, M.,Rudolph, J.
Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5-Fluoro-4-(3 H )-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor.
J.Med.Chem., 64:3940-3955, 2021

PubMed Abstract: Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (), which features a fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this hinge binder allows for a greater contribution of RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution of fluorine at the C5 position efficiently masked the adjacent polar NH functionality and increased solubility by impeding a solid-state conformation associated with stronger crystal packing of the molecule. The resulting improvements in permeability and solubility enabled oral dosing of . In vivo evaluation of in combination with the MEK inhibitor cobimetinib demonstrated synergistic pathway inhibition and significant tumor growth inhibition in a KRAS mutant xenograft mouse model.

PubMed: 33780623
DOI: 10.1021/acs.jmedchem.0c02085

Experimental method

X-RAY DIFFRACTION (1.93 Å)