Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapy

Bioorg Med Chem. 2017 Aug 1;25(15):4100-4109. doi: 10.1016/j.bmc.2017.05.058. Epub 2017 May 31.


Olaparib was the first PARP inhibitor approved by the FDA for patients with BRCA-mutated ovarian cancer. Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of olaparib and HDAC inhibitors. Herein, based on rational drug design strategy, hydroxamic acid derivatives of olaparib were constructed as dual PARP and HDAC inhibitors. These hybrid compounds showed potent inhibitory activities against PARP1/2 and HDAC1/6 with IC50 values in the nanomolar range. Furthermore, compound P1 exhibited broad-spectrum antiproliferative activities in selected human cancer cell lines. Specially, P1 showed more potent activity than olaparib and SAHA in cancer cells MDA-MB-231, HCC1937 and Raji, and 4.1-fold less cytotoxicity compared with SAHA to normal cells MCF-10A. Further mechanism study indicated that P1 could induce the cleavage of PARP and the hyperacetylation of histones, increase the expression of DNA damage biomarker γ-H2AX, decrease the level of BRCA1 and RAD51, and regulate tumor cell growth and apoptosis through modulating both mitochondrial- and death receptor-mediated pathways. Therefore, our study suggested that compounds targeting PARP and HDAC concurrently might be a practical approach for cancer therapy.

Keywords: Antitumor; Drug design; HDAC; Multitarget; PARP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / chemistry*
  • Magnetic Resonance Spectroscopy
  • Molecular Docking Simulation
  • Mutagenicity Tests
  • Phthalazines / chemistry
  • Phthalazines / pharmacology*
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Spectrometry, Mass, Electrospray Ionization


  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • olaparib