2. Academic Validation
  3. First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids

First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids

  • J Med Chem. 2022 Nov 10;65(21):14764-14791. doi: 10.1021/acs.jmedchem.2c01276.
Endri Karaj 1,  Shaimaa H Sindi 1,  Nishanth Kuganesan 2,  Radhika A Koranne 2,  Joseph R Knoff 3,  Antonisamy William James 1,  Yu Fu 1,  Lauren N Kotsull 3,  Mary Kay Pflum 3,  Zahoor Shah 1,  William R Taylor 2,  L M Viranga Tillekeratne 1
Affiliations

Affiliations

  • 1 Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio 43606, United States.
  • 2 Department of Biological Sciences, College of Natural Sciences and Mathematics, University of Toledo, Toledo, Ohio 43606, United States.
  • 3 Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States.
PMID: 36306372 DOI: 10.1021/acs.jmedchem.2c01276
Abstract

HDAC inhibitors are an attractive class of cytotoxic agents for the design of hybrid molecules. Several HDAC hybrids have emerged over the years, but none combines HDAC inhibition with Ferroptosis, a combination which is being extensively studied because it leads to enhanced cytotoxicity and attenuated neuronal toxicity. We combined the pharmacophores of SAHA and CETZOLE molecules to design the first-in-class dual mechanism hybrid molecules, which induce Ferroptosis and inhibit HDAC proteins. The involvement of both mechanisms in cytotoxicity was confirmed by a series of biological assays. The cytotoxic effects were evaluated in a series of Cancer and neuronal cell lines. Analogue HY-1 demonstrated the best cytotoxic profile with GI50 values as low as 20 nM. Although the increase in activity of the hybrids over the combinations is modest in cellular systems, they have the potential advantage of homogeneous spatiotemporal distribution in in vivo systems.

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