title: Discovery and Bioevaluation of Novel Pyrazolopyrimidine Analogs as Competitive Hsp90 Inhibitors Through Shape-Based Similarity Screening.
abstract: Hsp90 as a promising therapeutic target for the treatment of cancer has received great attention. Many Hsp90 inhibitors such as BIIB021 and CUDC-305 have been in clinical. In this paper shape-based similarity screening through ROCS overlays on the basis of CUDC-305, BIIB021, PU-H71 and PU-3 were performed to discover HSP90 inhibitors. A set of 19 novel pyrazolopyrimidine analogues was identified and evaluated on enzyme level and cell-based level as Hsp90 inhibitors. The compound HDI4-04 with IC50 0.35 µM in the Hsp90 ATP hydrolysis assay exhibited potent cytotoxicity against five human cancer cell lines. Western blot analysis and Hsp70 luciferase reporter assay further confirmed that HDI4-04 targeted the Hsp90 protein folding machinery. And according to the biological assay, the SAR was discussed and summarized, which will guide us for further optimization of these compounds.
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, P. R. China fax & tel: +86-25-83271351.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, P. R. China fax & tel: +86-25-83271351.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.|Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, P. R. China fax & tel: +86-25-83271216.
authors.forename: Hao-Peng
authors.initials: HP
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, P. R. China fax & tel: +86-25-83271351.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, P. R. China fax & tel: +86-25-83271351.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Jia
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, P. R. China fax & tel: +86-25-83271351.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Xiao-Ke
authors.initials: XK
authors.lastname: Guo
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, P. R. China fax & tel: +86-25-83271351.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, P. R. China fax & tel: +86-25-83271351.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Hao-Ze
authors.initials: HZ
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, P. R. China fax & tel: +86-25-83271351.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.|Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Xiao-Jin
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, P. R. China fax & tel: +86-25-83271351. sunhaopeng@163.com, youqidong@gmail.com.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China. sunhaopeng@163.com, youqidong@gmail.com.|Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, P. R. China fax & tel: +86-25-83271216. sunhaopeng@163.com, youqidong@gmail.com.
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
keywords: Breast cancer; Drug discovery; Heat shock protein 90; Hsp90 inhibitors; Purine; ROCS overlays; Virtual screening