Rational design, synthesis and biological profiling of new KDM4C inhibitors. Issue 1 (1st January 2020)

• Record Type: Journal Article
• Authors: Letfus, Vatroslav; Jelić, Dubravko; Bokulić, Ana; Petrinić Grba, Adriana; Koštrun, Sanja
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 1(2020)
• Publication Date: 2020-01-01
• Subjects: Epigenetics -- KDM4C enzyme -- Inhibitor -- Drug design -- Computational chemistry; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115128
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.