2. Academic Validation
  3. Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening

Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening

  • Eur J Med Chem. 2014 May 22:79:399-412. doi: 10.1016/j.ejmech.2014.03.061.
Hao-Peng Sun 1,  Jian-Min Jia 2,  Fen Jiang 2,  Xiao-Li Xu 2,  Fang Liu 2,  Xiao-Ke Guo 2,  Bahidja Cherfaoui 2,  Hao-Ze Huang 2,  Yang Pan 2,  Qi-Dong You 3
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqidong@gmail.com.
PMID: 24763261 DOI: 10.1016/j.ejmech.2014.03.061
Abstract

Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel HSP90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited HSP90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of HSP90 inhibitors. 57h can be ideal leads for further optimization.

Keywords

Design and synthesis; Hsp90 inhibitors; ROCS.

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