Optimization of Diarylthiazole B‐Raf Inhibitors: Identification of a Compound Endowed with High Oral Antitumor Activity,Mitigated hERG Inhibition,and Low Paradoxical Effect |
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| Authors: | Dr. Maurizio Pulici Dr. Gabriella Traquandi Dr. Chiara Marchionni Dr. Michele Modugno Dr. Rosita Lupi Nadia Amboldi Dr. Elena Casale Dr. Nicoletta Colombo Luca Corti Dr. Marina Fasolini Dr. Fabio Gasparri Wilma Pastori Dr. Alessandra Scolaro Dr. Daniele Donati Dr. Eduard Felder Dr. Arturo Galvani Dr. Antonella Isacchi Dr. Enrico Pesenti Dr. Marina Ciomei |
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| Affiliation: | Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano (MI) (Italy) |
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| 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 R1 and R2 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. |
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| Keywords: | antitumor agents B‐Raf inhibitors sulfonamides thiazoles |
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