Rational design, synthesis and biological profiling of new KDM4C inhibitors

  • Bioorg Med Chem. 2020 Jan 1;28(1):115128. doi: 10.1016/j.bmc.2019.115128.
Vatroslav Letfus  1 ,  Dubravko Jelić  2 ,  Ana Bokulić  2 ,  Adriana Petrinić Grba  2 ,  Sanja Koštrun  2
Affiliations
  • 1. Fidelta Ltd., Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia. Electronic address: [email protected].
  • 2. Fidelta Ltd., Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia.
PMID: 31784197 DOI: 10.1016/j.bmc.2019.115128
Abstract

The human histone demethylases of the KDM4 family have been related to diseases such as prostate and breast Cancer. Majority of currently known inhibitors suffer from the low permeability and low selectivity between the enzyme isoforms. In this study, toxoflavin motif was used to design and synthesize new KDM4C inhibitors with improved biological activity and in vitro ADME properties. Inhibitors displayed good passive cellular permeability and metabolic stability. However, diminishing of redox liability and consequently non-specific influence on cell viability still remains a challenge.

Keywords
Computational chemistry; Drug design; Epigenetics; Inhibitor; KDM4C enzyme.
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