5GGZ

Crystal structure of novel inhibitor bound with Hsp90

Summary for 5GGZ

• Entry DOI: 10.2210/pdb5ggz/pdb
• Descriptor: Heat shock protein HSP 90-alpha, [2,4-bis(oxidanyl)-5-propan-2-yl-phenyl]-(2-ethoxy-7,8-dihydro-5~{H}-pyrido[4,3-d]pyrimidin-6-yl)methanone (3 entities in total)
• Functional Keywords: hsp90, chaperone-chaperone inhibitor complex, chaperone/chaperone inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P07900
• Total number of polymer chains: 4
• Total formula weight: 95628.62

Authors

Chen, T.T.,Li, J.,Xu, Y.C. (deposition date: 2016-06-16, release date: 2017-03-08, Last modification date: 2024-03-20)

Primary citation

Jiang, F.,Wang, H.J.,Jin, Y.H.,Zhang, Q.,Wang, Z.H.,Jia, J.M.,Liu, F.,Wang, L.,Bao, Q.C.,Li, D.D.,You, Q.D.,Xu, X.L.
Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90
J. Med. Chem., 59:10498-10519, 2016

PubMed Abstract: Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.

PubMed: 27933959
DOI: 10.1021/acs.jmedchem.6b00912

Experimental method

X-RAY DIFFRACTION (2.015 Å)