title: Novel 3-methylindoline inhibitors of EZH2: Design, synthesis and SAR.
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.
authors.affiliation: Integral BioSciences Pvt. Ltd., C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Amantullah
authors.initials: A
authors.lastname: Ansari
authors.affiliation: Integral BioSciences Pvt. Ltd., C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Sharad
authors.initials: S
authors.lastname: Satalkar
authors.affiliation: Integral BioSciences Pvt. Ltd., C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Varshavekumar
authors.initials: V
authors.lastname: Patil
authors.affiliation: Integral BioSciences Pvt. Ltd., C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Shete
authors.affiliation: Integral BioSciences Pvt. Ltd., C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Simranjeet
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Integral BioSciences Pvt. Ltd., C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Ashu
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Integral BioSciences Pvt. Ltd., C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Singh
authors.affiliation: Integral BioSciences Pvt. Ltd., C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Mohd
authors.initials: M
authors.lastname: Raja
authors.affiliation: Schrodinger, Inc., Portland, OR, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Severance
authors.affiliation: Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Bernales
authors.affiliation: Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: Sarvajit
authors.initials: S
authors.lastname: Chakravarty
authors.affiliation: Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Hung
authors.affiliation: Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: Son M
authors.initials: SM
authors.lastname: Pham
authors.affiliation: Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Herrera
authors.affiliation: Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA. Electronic address: roopa.rai@hotmail.com.
authors.forename: Roopa
authors.initials: R
authors.lastname: Rai
mesh_terms: D000818:Animals; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; C103523:EZH1 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: Anticancer; EZH2; Indoline; Methyltransferases