4CQE

B-Raf Kinase V600E mutant in complex with a diarylthiazole B-Raf Inhibitor

Summary for 4CQE

• Entry DOI: 10.2210/pdb4cqe/pdb
• Descriptor: SLC45A3-BRAF FUSION PROTEIN, N-{4-[2-(1-cyclopropylpiperidin-4-yl)-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-5-yl]pyridin-2-yl}acetamide (3 entities in total)
• Functional Keywords: transferase, inhibitor complex
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 64481.88

Authors

Casale, E.,Fasolini, M.,Pulici, M.,Traquandi, G.,Marchionni, C.,Modugno, M.,Lupi, R.,Amboldi, N.,Colombo, N.,Corti, L.,Gasparri, F.,Pastori, W.,Scolaro, A.,Donati, D.,Felder, E.,Galvani, A.,Isacchi, A.,Pesenti, E.,Ciomei, M. (deposition date: 2014-02-14, release date: 2014-12-10, Last modification date: 2023-12-20)

Primary citation

Pulici, M.,Traquandi, G.,Marchionni, C.,Modugno, M.,Lupi, R.,Amboldi, N.,Casale, E.,Colombo, N.,Corti, L.,Fasolini, M.,Gasparri, F.,Pastori, W.,Scolaro, A.,Donati, D.,Felder, E.,Galvani, A.,Isacchi, A.,Pesenti, E.,Ciomei, M.
Optimization of Diarylthiazole B-Raf Inhibitors: Identification of a Compound Endowed with High Oral Antitumor Activity, Mitigated Herg Inhibition, and Low Paradoxical Effect.
Chemmedchem, 10:276-, 2015

PubMed Abstract: Aberrant activation of the mitogen-activated protein kinase (MAPK)-mediated pathway components, RAF-MEK-ERK, is frequently observed in human cancers and clearly contributes to oncogenesis. As part of a project aimed at finding inhibitors of B-Raf, a key player in the MAPK cascade, we originally identified a thiazole derivative endowed with high potency and selectivity, optimal in vitro ADME properties, and good pharmacokinetic profiles in rodents, but that suffers from elevated hERG inhibitory activity. An optimization program was thus undertaken, focused mainly on the elaboration of the R(1) and R(2) groups of the scaffold. This effort ultimately led to N-(4-{2-(1-cyclopropylpiperidin-4-yl)-4-[3-(2,5-difluorobenzenesulfonylamino)-2-fluorophenyl]thiazol-5-yl}-pyridin-2-yl)acetamide (20), which maintains favorable in vitro and in vivo properties, but lacks hERG liability. Besides exhibiting potent antiproliferative activity against only cell lines bearing B-Raf V600E or V600D mutations, compound 20 also intriguingly shows a weaker "paradoxical" activation of MEK in non-mutant B-Raf cells than other known B-Raf inhibitors. It also demonstrates very good efficacy in vivo against the A375 xenograft melanoma model (tumor volume inhibition >90% at 10 mg kg(-1) ); it is therefore a suitable candidate for preclinical development.

PubMed: 25430902
DOI: 10.1002/CMDC.201402424

Experimental method

X-RAY DIFFRACTION (2.3 Å)