2. Academic Validation
  3. Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors

Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors

  • Bioorg Med Chem Lett. 2012 Jan 15;22(2):1136-41. doi: 10.1016/j.bmcl.2011.11.100.
Atsushi Suda 1,  Hiroshi Koyano,  Tadakatsu Hayase,  Kihito Hada,  Ken-Ichi Kawasaki,  Susumu Komiyama,  Kiyoshi Hasegawa,  Takaaki A Fukami,  Shigeo Sato,  Takaaki Miura,  Naomi Ono,  Toshikazu Yamazaki,  Ryoichi Saitoh,  Nobuo Shimma,  Yasuhiko Shiratori,  Takuo Tsukuda
Affiliations

Affiliation

  • 1 Kamakura Laboratories, Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. sudaats@chugai-pharm.co.jp
PMID: 22192591 DOI: 10.1016/j.bmcl.2011.11.100
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%).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15990
    Hsp90a Inhibitor
    HSP