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Bioorg Med Chem Lett. 2017 Jan 15;27(2):217-222. doi: 10.1016/j.bmcl.2016.11.080. Epub 2016 Nov 25.

Novel 3-methylindoline inhibitors of EZH2: Design, synthesis and SAR.

Author information

1
Integral BioSciences Pvt. Ltd., C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
2
Schrodinger, Inc., Portland, OR, USA.
3
Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
4
Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA. Electronic address: roopa.rai@hotmail.com.

Abstract

EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2 inhibition has emerged as a promising therapeutic target. Several small molecule EZH2 inhibitors with different chemotypes have been reported in the literature, many of which use a bicyclic heteroaryl core. Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core. Partial saturation of an indole to an indoline provided lead compounds with nanomolar activity against EZH2, while also improving solubility and oxidative metabolic stability.

KEYWORDS:

Anticancer; EZH2; Indoline; Methyltransferases

PMID:
27923618
DOI:
10.1016/j.bmcl.2016.11.080
[Indexed for MEDLINE]

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