2. Academic Validation
  3. Design, synthesis and biological evaluation of biphenylamide derivatives as Hsp90 C-terminal inhibitors

Design, synthesis and biological evaluation of biphenylamide derivatives as Hsp90 C-terminal inhibitors

  • Eur J Med Chem. 2015 Jan 7:89:442-66. doi: 10.1016/j.ejmech.2014.10.034.
Huiping Zhao 1,  Gaurav Garg 1,  Jinbo Zhao 1,  Elisabetta Moroni 2,  Antwan Girgis 1,  Lucas S Franco 1,  Swapnil Singh 1,  Giorgio Colombo 2,  Brian S J Blagg 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, KS 66045-7563, USA.
  • 2 Istituto di chimica del riconoscimento molecolare, CNR, Via Mario Bianco 9, 20131 Milano, Italy.
  • 3 Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, KS 66045-7563, USA. Electronic address: [email protected].
PMID: 25462258 DOI: 10.1016/j.ejmech.2014.10.034
Abstract

Modulation of HSP90 C-terminal function represents a promising therapeutic approach for the treatment of Cancer and neurodegenerative diseases. Current drug discovery efforts toward HSP90 C-terminal inhibition focus on novobiocin, an Antibiotic that was transformed into an HSP90 Inhibitor. Based on structural information obtained during the development of novobiocin derivatives and molecular docking studies, scaffolds containing a biphenyl moiety in lieu of the coumarin ring present in novobiocin were identified as new HSP90 C-terminal inhibitors. Structure-activity relationship studies produced new derivatives that inhibit the proliferation of breast Cancer cell lines at nanomolar concentrations, which corresponded directly with HSP90 inhibition.

Keywords

Biphenyl; Breast cancer; Heat shock protein 90; Hsp90 C-Terminal inhibitors; Structure–activity relationship.

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