title: Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent.
abstract: The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D-structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study.
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, Kamakura, Kanagawa, Japan. isshikiysa@chugai-pharm.co.jp
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Isshiki
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kohchi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iikura
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Matsubara
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Asoh
authors.forename: Takeshi
authors.initials: T
authors.lastname: Murata
authors.forename: Masami
authors.initials: M
authors.lastname: Kohchi
authors.forename: Eisaku
authors.initials: E
authors.lastname: Mizuguchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsujii
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hattori
authors.forename: Takaaki
authors.initials: T
authors.lastname: Miura
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Aida
authors.forename: Masanori
authors.initials: M
authors.lastname: Miwa
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Saitoh
authors.forename: Naoaki
authors.initials: N
authors.lastname: Murao
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Okabe
authors.forename: Charles
authors.initials: C
authors.lastname: Belunis
authors.forename: Cheryl
authors.initials: C
authors.lastname: Janson
authors.forename: Christine
authors.initials: C
authors.lastname: Lukacs
authors.forename: Verena
authors.initials: V
authors.lastname: Schück
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D010078:Oxazines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C559138:CH 4987655; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D020930:MAP Kinase Kinase Kinases