3WHA

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

Summary for 3WHA

• Entry DOI: 10.2210/pdb3wha/pdb
• Related: 3B28
• Descriptor: Heat shock protein HSP 90-alpha, GLYCEROL, 4-{[4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazin-2-yl]sulfanyl}butanamide, ... (5 entities in total)
• Functional Keywords: chaperone, chaperone-chaperone inhibitor complex, chaperone/chaperone inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P07900
• Total number of polymer chains: 2
• Total formula weight: 52524.12

Authors

Fukami, T.A.,Ono, N. (deposition date: 2013-08-23, release date: 2014-01-29, Last modification date: 2023-11-08)

Primary citation

Suda, A.,Kawasaki, K.,Komiyama, S.,Isshiki, Y.,Yoon, D.-O.,Kim, S.-J.,Na, Y.-J.,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 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors
Bioorg.Med.Chem., 22:892-905, 2014

PubMed 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%).

PubMed: 24369839
DOI: 10.1016/j.bmc.2013.11.036

Experimental method

X-RAY DIFFRACTION (1.3 Å)