3B24

Hsp90 alpha N-terminal domain in complex with an aminotriazine fragment molecule

Summary for 3B24

• Entry DOI: 10.2210/pdb3b24/pdb
• Related: 3B25 3B26 3B27 3B28
• Descriptor: Heat shock protein HSP 90-alpha, MAGNESIUM ION, 4-(ethylsulfanyl)-6-methyl-1,3,5-triazin-2-amine, ... (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: 2
• Total formula weight: 51940.71

Authors

Fukami, T.A.,Ono, N. (deposition date: 2011-07-21, release date: 2011-09-14, Last modification date: 2024-03-13)

Primary citation

Miura, T.,Fukami, T.A.,Hasegawa, K.,Ono, N.,Suda, A.,Shindo, H.,Yoon, D.O.,Kim, S.J.,Na, Y.J.,Aoki, Y.,Shimma, N.,Tsukuda, T.,Shiratori, Y.
Lead generation of heat shock protein 90 inhibitors by a combination of fragment-based approach, virtual screening, and structure-based drug design
Bioorg.Med.Chem.Lett., 21:5778-5783, 2011

PubMed 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.

PubMed: 21875802
DOI: 10.1016/j.bmcl.2011.08.001

Experimental method

X-RAY DIFFRACTION (1.7 Å)