Optimization of Diarylthiazole B‐Raf Inhibitors: Identification of a Compound Endowed with High Oral Antitumor Activity, Mitigated hERG Inhibition, and Low Paradoxical Effect. Issue 2 (27th November 2014)

• Record Type: Journal Article
• Authors: Pulici, Maurizio; Traquandi, Gabriella; Marchionni, Chiara; Modugno, Michele; Lupi, Rosita; Amboldi, Nadia; Casale, Elena; Colombo, Nicoletta; Corti, Luca; Fasolini, Marina; Gasparri, Fabio; Pastori, Wilma; Scolaro, Alessandra; Donati, Daniele; Felder, Eduard; Galvani, Arturo; Isacchi, Antonella; Pesenti, Enrico; Ciomei, Marina
• Is Part Of: ChemMedChem. Volume 10:Issue 2(2015:Feb.)
• Page Start: 276
• Page End: 295
• Publication Date: 2014-11-27
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201402424
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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<sup>1</sup> and R<sup>2</sup> groups of the scaffold. This effort ultimately led to <italic>N</italic>‐(4‐{2‐(1‐cyclopropylpiperidin‐4‐yl)‐4‐[3‐(2, 5‐difluorobenzenesulfonylamino)‐2‐fluorophenyl]thiazol‐5‐yl}‐pyridin‐2‐yl)acetamide (<bold>20</bold>), 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 <bold>20</bold> 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<sup>−1</sup>); it is therefore a suitable candidate for preclinical development.</p> </abstract>