title: Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors.
abstract: A novel series of 2-amino-1,3,5-triazines bearing a tricyclic moiety as heat shock protein 90 (Hsp90) inhibitors is described. Molecular design was performed using X-ray cocrystal structures of the lead compound CH5015765 and natural Hsp90 inhibitor geldanamycin with Hsp90. We optimized affinity to Hsp90, in vitro cell growth inhibitory activity, water solubility, and liver microsomal stability of inhibitors and identified CH5138303. This compound showed high binding affinity for N-terminal Hsp90α (Kd=0.52nM) and strong in vitro cell growth inhibition against human cancer cell lines (HCT116 IC50=0.098μM, NCI-N87 IC50=0.066μM) and also displayed high oral bioavailability in mice (F=44.0%) and potent antitumor efficacy in a human NCI-N87 gastric cancer xenograft model (tumor growth inhibition=136%).
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. Electronic address: sudaats@chugai-pharm.co.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suda
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Kawasaki
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Komiyama
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Isshiki
authors.affiliation: Discovery Research Center, C&C Research Laboratories, DRC Natural Sciences Campus, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do 440-746, Republic of Korea.
authors.forename: Dong-Oh
authors.initials: DO
authors.lastname: Yoon
authors.affiliation: Discovery Research Center, C&C Research Laboratories, DRC Natural Sciences Campus, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do 440-746, Republic of Korea.
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Discovery Research Center, C&C Research Laboratories, DRC Natural Sciences Campus, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do 440-746, Republic of Korea.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Na
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Takaaki A
authors.initials: TA
authors.lastname: Fukami
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Sato
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Miura
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Ono
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Saitoh
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Shiratori
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Tsukuda
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D018841:HSP90 Heat-Shock Proteins; D014227:Triazines
keywords: Antitumor agent; Hsp90 inhibitor; Lead optimization; Structure-based drug design