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Atsushi Suda,
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
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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%).
Bioorganic & medicinal chemistry letters 12/2011; 22(2):1136-41. · 2.65 Impact Factor
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Takaaki Miura,
Takaaki A Fukami, Kiyoshi Hasegawa,
Naomi Ono,
Atsushi Suda,
Hidetoshi Shindo,
Dong-Oh Yoon,
Sung-Jin Kim,
Young-Jun Na,
Yuko Aoki,
Nobuo Shimma,
Takuo Tsukuda,
Yasuhiko Shiratori
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ABSTRACT: Heat shock protein 90 (Hsp90) is a molecular chaperone which regulates maturation and stabilization of its substrate proteins, known as client proteins. Many client proteins of Hsp90 are involved in tumor progression and survival and therefore Hsp90 can be a good target for developing anticancer drugs. With the aim of efficiently identifying a new class of orally available inhibitors of the ATP binding site of this protein, we conducted fragment screening and virtual screening in parallel against Hsp90. This approach quickly identified 2-aminotriazine and 2-aminopyrimidine derivatives as specific ligands to Hsp90 with high ligand efficiency. In silico evaluation of the 3D X-ray Hsp90 complex structures of the identified hits allowed us to promptly design CH5015765, which showed high affinity for Hsp90 and antitumor activity in human cancer xenograft mouse models.
Bioorganic & medicinal chemistry letters 08/2011; 21(19):5778-83. · 2.65 Impact Factor
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ABSTRACT: Pharmacokinetic (PK) parameters of N-myristoyltransferase (Nmt) inhibitors were measured, and a multivariate quantitative structure-pharmacokinetic relationship (QSPKR) model for predicting rat elimination half-life (t(1/2)) values was constructed. One hundred seven benzofuran derivatives have been selected as the data set for QSPKR analysis. The correlation between the t(1/2) values and 30 physicochemical descriptors was examined by a stepwise multiple linear regression method. The statistical analysis gives a significant QSPKR model (r = 0.843) with the following three variables: partial negative surface area (PNSA), atomic-based octanol/water partition coefficient (AlogP), and the number of rotational bonds (Rotlbonds). The QSPKR model obtained is predictive and simple, and would give a direction for designing new Nmt inhibitors having good PK profiles.
Journal of Chemical Information and Computer Sciences 06/2002; 42(4):968-75.
