2. Academic Validation
  3. Discovery of novel class of histone deacetylase inhibitors as potential anticancer agents

Discovery of novel class of histone deacetylase inhibitors as potential anticancer agents

  • Bioorg Med Chem. 2021 Jul 15:42:116251. doi: 10.1016/j.bmc.2021.116251.
Raafat El-Awady 1,  Ekram Saleh 2,  Rifat Hamoudi 3,  Wafaa S Ramadan 3,  Ralph Mazitschek 4,  Manal A Nael 5,  Khaled M Elokely 6,  Magid Abou-Gharbia 7,  Wayne E Childers 7,  Vunnam Srinivasulu 8,  Lujain Aloum 9,  Varsha Menon 8,  Taleb H Al-Tel 10
Affiliations

Affiliations

  • 1 Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates. Electronic address: relawady@sharjah.ac.ae.
  • 2 Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt.
  • 3 Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates.
  • 4 Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, United states.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt; Institute for Computational Molecular Science, and Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
  • 6 Institute for Computational Molecular Science, and Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
  • 7 Moulder Center for Drug Discovery Research, Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Phialadelphia, PA 19122, United States.
  • 8 Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates.
  • 9 Department of Pharmacology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi 127788, United Arab Emirates.
  • 10 Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates. Electronic address: taltal@sharjah.ac.ae.
PMID: 34116381 DOI: 10.1016/j.bmc.2021.116251
Abstract

Selective inhibition of histone deacetylases (HDACs) is an important strategy in the field of Anticancer drug discovery. However, lack of inhibitors that possess high selectivity toward certain HDACs isozymes is associated with adverse side effects that limits their clinical applications. We have initiated a collaborative initiatives between multi-institutions aimed at the discovery of novel and selective HDACs inhibitors. To this end, a phenotypic screening of an in-house pilot library of about 70 small molecules against various HDAC isozymes led to the discovery of five compounds that displayed varying degrees of HDAC isozyme selectivity. The Anticancer activities of these molecules were validated using various biological assays including transcriptomic studies. Compounds 15, 14, and 19 possessed selective inhibitory activity against HDAC5, while 28 displayed selective inhibition of HDAC1 and HDAC2. Compound 22 was found to be a selective inhibitor for HDAC3 and HDAC9. Importantly, we discovered a none-hydroxamate based HDAC Inhibitor, compound 28, representing a distinct chemical probe of HDAC inhibitors. It contains a trifluoromethyloxadiazolyl moiety (TFMO) as a non-chelating metal-binding group. The new compounds showed potent anti-proliferative activity when tested against MCF7 breast Cancer cell line, as well as increased acetylation of histones and induce cells Apoptosis. The new compounds apoptotic effects were validated through the upregulation of proapoptotic proteins caspases3 and 7 and downregulation of the antiapoptotic biomarkers c-Myc, BCL2, BCL3 and NFĸB genes. Furthermore, the new compounds arrested cell cycle at different phases, which was confirmed through downregulation of the CDK1, 2, 4, 6, E2F1 and RB1 proteins. Taken together, our findings provide the foundation for the development of new chemical probes as potential lead drug candidates for the treatment of Cancer.

Keywords

Anticancer; Apoptosis; Cell cycle; Groebke‐Blackburn‐Bienaymé reaction; Histone deacetylase inhibitors; Imidazopyridines; Multicomponent reactions; Transcriptomic.

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