3b27

Publication Abstract from PubMed

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.

Lead generation of heat shock protein 90 inhibitors by a combination of fragment-based approach, virtual screening, and structure-based drug design.,Miura T, Fukami TA, Hasegawa K, Ono N, Suda A, Shindo H, Yoon DO, Kim SJ, Na YJ, Aoki Y, Shimma N, Tsukuda T, Shiratori Y Bioorg Med Chem Lett. 2011 Oct 1;21(19):5778-83. Epub 2011 Aug 6. PMID:21875802^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.