title: Optimization of diarylthiazole B-raf inhibitors: identification of a compound endowed with high oral antitumor activity, mitigated hERG inhibition, and low paradoxical effect.
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.
authors.affiliation: Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano (MI) (Italy). maurizio.pulici@nervianoms.com.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pulici
authors.forename: Gabriella
authors.initials: G
authors.lastname: Traquandi
authors.forename: Chiara
authors.initials: C
authors.lastname: Marchionni
authors.forename: Michele
authors.initials: M
authors.lastname: Modugno
authors.forename: Rosita
authors.initials: R
authors.lastname: Lupi
authors.forename: Nadia
authors.initials: N
authors.lastname: Amboldi
authors.forename: Elena
authors.initials: E
authors.lastname: Casale
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Colombo
authors.forename: Luca
authors.initials: L
authors.lastname: Corti
authors.forename: Marina
authors.initials: M
authors.lastname: Fasolini
authors.forename: Fabio
authors.initials: F
authors.lastname: Gasparri
authors.forename: Wilma
authors.initials: W
authors.lastname: Pastori
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scolaro
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Eduard
authors.initials: E
authors.lastname: Felder
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Marina
authors.initials: M
authors.lastname: Ciomei
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C000601546:N-(4-(2-(1-cyclopropylpiperidin-4-yl)-4-(3-(2,5-difluorobenzenesulfonylamino)-2-fluorophenyl)thiazol-5-yl)pyridin-2-yl)acetamide; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013844:Thiazoles; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human
keywords: B-Raf inhibitors; antitumor agents; sulfonamides; thiazoles