SAH derived potent and selective EZH2 inhibitors

Pei-Pei Kung; Buwen Huang; Luke Zehnder; John Tatlock; Patrick Bingham; Cody Krivacic; Ketan Gajiwala; Wade Diehl; Xiu Yu; Karen A Maegley

doi:10.1016/j.bmcl.2015.02.017

SAH derived potent and selective EZH2 inhibitors

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1532-7. doi: 10.1016/j.bmcl.2015.02.017. Epub 2015 Feb 17.

Authors

Affiliations

¹ Oncology Chemistry, Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr., San Diego, CA 92121, USA.
² Oncology Research Unit, Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr., San Diego, CA 92121, USA.

PMID: 25746813
DOI: 10.1016/j.bmcl.2015.02.017

Abstract

A series of novel enhancer of zeste homolog 2 (EZH2) inhibitors was designed based on the chemical structure of the histone methyltransferase (HMT) inhibitor SAH (S-adenosyl-l-homocysteine). These nucleoside-based EZH2 inhibitors blocked the methylation of nucleosomes at H3K27 in biochemical assays employing both WT PRC2 complex as well as a Y641N mutant PRC2 complex. The most potent compound, 27, displayed IC50's against both complexes of 270 nM and 70 nM, respectively. To our knowledge, compound 27 is the most potent SAH-derived inhibitor of the EZH2 PRC2 complex yet identified. This compound also displayed improved potency, lipophilic efficiency (LipE), and selectivity profile against other lysine methyltransferases compared with SAH.

Keywords: EZH2; Homology model; Nucleoside; SAH.

MeSH terms

Dose-Response Relationship, Drug
Drug Design
Enhancer of Zeste Homolog 2 Protein
Humans
Models, Molecular
Molecular Structure
Polycomb Repressive Complex 2 / antagonists & inhibitors*
S-Adenosylhomocysteine / chemical synthesis
S-Adenosylhomocysteine / chemistry
S-Adenosylhomocysteine / pharmacology*
Structure-Activity Relationship

Substances

S-Adenosylhomocysteine
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2