title: SAR156497, an exquisitely selective inhibitor of aurora kinases.
abstract: The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.
authors.affiliation: Oncology Drug Discovery, ‡Structure Design Informatics, §Disposition Safety Animal Research, ∥Chemical Development, and ⊥Analytical Sciences, Sanofi , 13 Quai Jules Guesde, 94403 Vitry-sur-Seine, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Carry
authors.forename: François
authors.initials: F
authors.lastname: Clerc
authors.forename: Hervé
authors.initials: H
authors.lastname: Minoux
authors.forename: Laurent
authors.initials: L
authors.lastname: Schio
authors.forename: Jacques
authors.initials: J
authors.lastname: Mauger
authors.forename: Anil
authors.initials: A
authors.lastname: Nair
authors.forename: Eric
authors.initials: E
authors.lastname: Parmantier
authors.forename: Ronan
authors.initials: R
authors.lastname: Le Moigne
authors.forename: Cécile
authors.initials: C
authors.lastname: Delorme
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Nicolas
authors.forename: Alain
authors.initials: A
authors.lastname: Krick
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Abécassis
authors.forename: Véronique
authors.initials: V
authors.lastname: Crocq-Stuerga
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Pouzieux
authors.forename: Laure
authors.initials: L
authors.lastname: Delarbre
authors.forename: Sébastien
authors.initials: S
authors.lastname: Maignan
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertrand
authors.forename: Kirsten
authors.initials: K
authors.lastname: Bjergarde
authors.forename: Nina
authors.initials: N
authors.lastname: Ma
authors.forename: Sylvette
authors.initials: S
authors.lastname: Lachaud
authors.forename: Houlfa
authors.initials: H
authors.lastname: Guizani
authors.forename: Rémi
authors.initials: R
authors.lastname: Lebel
authors.forename: Gilles
authors.initials: G
authors.lastname: Doerflinger
authors.forename: Sylvie
authors.initials: S
authors.lastname: Monget
authors.forename: Sébastien
authors.initials: S
authors.lastname: Perron
authors.forename: Francis
authors.initials: F
authors.lastname: Gasse
authors.forename: Odile
authors.initials: O
authors.lastname: Angouillant-Boniface
authors.forename: Bruno
authors.initials: B
authors.lastname: Filoche-Rommé
authors.forename: Michel
authors.initials: M
authors.lastname: Murer
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gontier
authors.forename: Céline
authors.initials: C
authors.lastname: Prévost
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Monteiro
authors.forename: Cécile
authors.initials: C
authors.lastname: Combeau
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D064108:Aurora Kinase C / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D016513:Mice, SCID; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D015363:Quinolones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D061987:Sf9 Cells; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D054852:Small Molecule Libraries; C000597231:ethyl 8-oxo-9-(3-(1H-benzimidazol-2-yloxy)phenyl)-4,5,6,7,8,9-hexahydro-2H-pyrrolo(3,4-b)quinoline-3-carboxylate; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064108:Aurora Kinase C; D064127:Aurora Kinases