3VHC

Hsp90 alpha N-terminal domain in complex with a macrocyclic inhibitor

Summary for 3VHC

• Entry DOI: 10.2210/pdb3vhc/pdb
• Related: 3B24 3B25 3B26 3B27 3B28 3VHA 3VHD
• Descriptor: Heat shock protein HSP 90-alpha, 4-amino-20,22-dimethyl-13-oxa-7-thia-3,5,17-triazatetracyclo[17.3.1.1~2,6~.1~8,12~]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-18-one, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: chaperone-chaperone inhibitor complex, chaperone/chaperone inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P07900
• Total number of polymer chains: 1
• Total formula weight: 26218.77

Authors

Fukami, T.A.,Ono, N. (deposition date: 2011-08-24, release date: 2012-07-18, Last modification date: 2024-03-20)

Primary citation

Suda, A.,Koyano, H.,Hayase, T.,Hada, K.,Kawasaki, K.,Komiyama, S.,Hasegawa, K.,Fukami, T.A.,Sato, S.,Miura, T.,Ono, N.,Yamazaki, T.,Saitoh, R.,Shimma, N.,Shiratori, Y.,Tsukuda, T.
Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors
Bioorg.Med.Chem.Lett., 22:1136-1141, 2012

PubMed 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%).

PubMed: 22192591
DOI: 10.1016/j.bmcl.2011.11.100

Experimental method

X-RAY DIFFRACTION (1.41 Å)