title: Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors.
abstract: Macrocyclic compounds bearing a 2-amino-6-arylpyrimidine moiety were identified as potent heat shock protein 90 (Hsp90) inhibitors by modification of 2-amino-6-aryltriazine derivative (CH5015765). We employed a macrocyclic structure as a skeleton of new inhibitors to mimic the geldanamycin-Hsp90 interactions. Among the identified inhibitors, CH5164840 showed high binding affinity for N-terminal Hsp90α (K(d)=0.52nM) and strong anti-proliferative activity against human cancer cell lines (HCT116 IC(50)=0.15μM, NCI-N87 IC(50)=0.066μM). CH5164840 displayed high oral bioavailability in mice (F=70.8%) and potent antitumor efficacy in a HCT116 human colorectal cancer xenograft model (tumor growth inhibition=83%).
authors.affiliation: Kamakura Laboratories, Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. sudaats@chugai-pharm.co.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koyano
authors.forename: Tadakatsu
authors.initials: T
authors.lastname: Hayase
authors.forename: Kihito
authors.initials: K
authors.lastname: Hada
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Susumu
authors.initials: S
authors.lastname: Komiyama
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Takaaki A
authors.initials: TA
authors.lastname: Fukami
authors.forename: Shigeo
authors.initials: S
authors.lastname: Sato
authors.forename: Takaaki
authors.initials: T
authors.lastname: Miura
authors.forename: Naomi
authors.initials: N
authors.lastname: Ono
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Saitoh
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Shiratori
authors.forename: Takuo
authors.initials: T
authors.lastname: Tsukuda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D047028:Macrocyclic Compounds; D011743:Pyrimidines