Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7

Abstract

Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective,c ell-permeable inhibitors or suitable tool compounds for these enzymes.W ed escribe the discovery of an ew class of inhibitor that is highly potent towardst he histone lysine demethylases KDM2A/7A. Amodular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure-activity relationships, leading to the development of asmall molecule with around 75fold selectivity towards KDM2A/7A versus other KDMs,a s well as cellular activity at low micromolar concentrations.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.

Histone demethylase KDM2A: Biological functions and clinical values (Review)

“…Thus, there is great interest to investigate and identify selective and therapeutic KDMs inhibitors (37). Understanding the structure of lysine demethylases and their modular synthetic approach has helped design and develop a series of highly selective KDM2/7 inhibitors (38,39). Some inhibitors exhibit antiproliferative activity, and so may be used as candidates for anticancer agents (38).…”

Kinetic resolution of indolines by asymmetric hydroxylamine formation

“…Trans -2,3-trisubstituted indoline 8 was identified as a potent and selective inhibitor of the histone lysine demethylases KDM2A/7A (Fig. 5d ) 52 . Under the standard conditions, rac- 9 participated in the asymmetric oxygenation reaction, furnishing (2 R , 3 R )- 9 in 45% yield with 96% ee together with (2 S , 3 S )- 10 in 47% yield with 91% ee ( s = 85) (Fig.…”

Self-assembled coumarin- and 5-fluorouracil-PEG micelles as multifunctional drug delivery systems

“…Paclitaxel was provided by the Hospital General de Ciudad Real (Spain). 1-Azido-5-bromopentane (ABrP) was prepared according to a literature procedure [25,26]. 4-Azidomethyl-7-methoxycoumarin (AMMC) was prepared as described elsewhere by some of us [27].…”