Discovery, design, and synthesis of indole-based EZH2 inhibitors

Victor S Gehling; Rishi G Vaswani; Christopher G Nasveschuk; Martin Duplessis; Priyadarshini Iyer; Srividya Balasubramanian; Feng Zhao; Andrew C Good; Robert Campbell; Christina Lee; Les A Dakin; Andrew S Cook; Alexandre Gagnon; Jean-Christophe Harmange; James E Audia; Richard T Cummings; Emmanuel Normant; Patrick Trojer; Brian K Albrecht

doi:10.1016/j.bmcl.2015.06.056

Discovery, design, and synthesis of indole-based EZH2 inhibitors

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3644-9. doi: 10.1016/j.bmcl.2015.06.056. Epub 2015 Jun 19.

Authors

Victor S Gehling¹, Rishi G Vaswani², Christopher G Nasveschuk², Martin Duplessis², Priyadarshini Iyer², Srividya Balasubramanian², Feng Zhao², Andrew C Good², Robert Campbell², Christina Lee², Les A Dakin², Andrew S Cook², Alexandre Gagnon², Jean-Christophe Harmange², James E Audia², Richard T Cummings², Emmanuel Normant², Patrick Trojer², Brian K Albrecht²

Affiliations

¹ Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
² Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.

PMID: 26189078
DOI: 10.1016/j.bmcl.2015.06.056

Abstract

The discovery and optimization of a series of small molecule EZH2 inhibitors is described. Starting from dimethylpyridone HTS hit (2), a series of indole-based EZH2 inhibitors were identified. Biochemical potency and microsomal stability were optimized during these studies and afforded compound 22. This compound demonstrates nanomolar levels of biochemical potency (IC50=0.002 μM), cellular potency (EC50=0.080 μM), and afforded tumor regression when dosed (200 mpk SC BID) in an EZH2 dependent tumor xenograft model.

Keywords: EZH2; Epigenetics; Histone methyltransferase; PRC2; Pyridone.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Chemistry Techniques, Synthetic
Drug Design
Drug Discovery
Drug Screening Assays, Antitumor
Drug Stability
Enhancer of Zeste Homolog 2 Protein
HeLa Cells / drug effects
Humans
Indoles / chemistry*
Inhibitory Concentration 50
Mice
Molecular Targeted Therapy / methods
Polycomb Repressive Complex 2 / antagonists & inhibitors*
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Indoles
Small Molecule Libraries
indole
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2