2. Academic Validation
  3. Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapy

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.
Zigao Yuan 1,  Shaopeng Chen 2,  Qinsheng Sun 3,  Ning Wang 1,  Dan Li 1,  Shuangshuang Miao 2,  Chunmei Gao 4,  Yuzong Chen 5,  Chunyan Tan 2,  Yuyang Jiang 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 2 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 3 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China.
  • 4 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: chunmeigao@sz.tsinghua.edu.cn.
  • 5 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Bioinformatics and Drug Design Group, Department of Pharmacy, Centre for Computational Science and Engineering, National University of Singapore, 117543, Singapore.
  • 6 The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
PMID: 28601509 DOI: 10.1016/j.bmc.2017.05.058
Abstract

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.

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