Novel SAR for quinazoline inhibitors of EHMT1 and EHMT2

Bioorg Med Chem Lett. 2019 Sep 1;29(17):2516-2524. doi: 10.1016/j.bmcl.2019.06.012.

Ruben Leenders ¹, Remco Zijlmans ², Bart van Bree ², Marc van de Sande ², Federica Trivarelli ², Eddy Damen ², Anita Wegert ², Daniel Müller ³, Jan Erik Ehlert ³, Daniel Feger ³, Carolin Heidemann-Dinger ³, Michael Kubbutat ³, Christoph Schächtele ³, Danny C Lenstra ⁴, Jasmin Mecinović ⁴, Gerhard Müller ⁵

Affiliations

1 Mercachem BV, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands. Electronic address: ruben.leenders@mercachem.com.
2 Mercachem BV, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
3 ProQinase GmbH, Breisacher Strasse 117, 19106 Freiburg im Breisgau, Germany.
4 Radboud University, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
5 Gotham Therapeutics, 430 East 29th Street, New York, NY 10016, USA.

PMID: 31350126 DOI: 10.1016/j.bmcl.2019.06.012

Abstract

Detailed structure activity relationship of two series of quinazoline EHMT1/EHMT2 inhibitors (UNC0224 and UNC0638) have been elaborated. New and active alternatives are presented for the ubiquitous substitution patterns found in literature for the linker to the lysine mimicking region and the lysine mimic itself. These findings could allow for advancing EHMT1/EHMT2 inhibitors of that type beyond tool compounds by fine-tuning physicochemical properties making these inhibitors more drug-like. .

Keywords

EHMT1; EHMT2; Epigenetics; Histone Lysine Methyl Transferase (HMKT); Quinazoline.

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