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

Ansari, Amantullah; Satalkar, Sharad; Patil, Varshavekumar; Shete, Amit S.; Kaur, Simranjeet; Gupta, Amit; Singh, Siddhartha; Raja, Mohd.; Severance, Daniel L.; Bernales, Sebastián; Chakravarty, Sarvajit; Hung, David T.; Pham, Son M.; Herrera, Francisco; Rai, Roopa

doi:10.1016/j.bmcl.2016.11.080

Cited by 9 publications

(9 citation statements)

References 20 publications

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“…The cyclization of methyl and ethyl groups in these inhibitors might be lost of the "magic methyl" effect that has been reported in the literature. 22,23 Based on these results, we chose the most potent compound 11 for further SAR exploration.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The aniline 35 was then converted to the amide compounds 6−14 by treatment with acyl chloride. Indole 36 was reduced by triethylsilane 23 followed by N-Boc protection and Suzuki−Miyaura coupling reaction to yield the intermediate 39 (Scheme 2). Hydrolysis of the ester and subsequent amide coupling reaction resulted in amide 40, which was further converted to amine 41 by deprotection of the N-Boc group under acidic conditions.…”

Section: ■ Chemistrymentioning

confidence: 99%

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Discovery of IHMT-EZH2-115 as a Potent and Selective Enhancer of Zeste Homolog 2 (EZH2) Inhibitor for the Treatment of B-Cell Lymphomas

et al. 2021

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The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). Overexpression or mutation of EZH2 has been identified in hematologic malignancies and solid tumors. Based on the structure of EPZ6438 (1) and the binding model with PRC2, we designed a series of analogues aiming to improve the activities of EZH2 mutants. Structure–activity relationship (SAR) exploration at both enzymatic and cellular levels led to the discovery of inhibitor 29. In the biochemical assay, 29 inhibited EZH2 (IC50 = 26.1 nM) with high selectivity over other histone methyltransferases. It was also potent against EZH2 mutants (EZH2 Y641F, IC50 = 72.3 nM). Furthermore, it showed no apparent inhibitory activity against the human ether-á-go-go related gene (hERG) (IC50 > 30 μM). In vivo, 29 exhibited favorable pharmacokinetic properties for oral administration and showed better efficacy than 1 in both Pfeiffer and Karpas-422 cell-mediated xenograft mouse models, indicating that it might be a new potential therapeutic candidate for EZH2 mutant cancers.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Chemistrymentioning

confidence: 99%

Discovery of IHMT-EZH2-115 as a Potent and Selective Enhancer of Zeste Homolog 2 (EZH2) Inhibitor for the Treatment of B-Cell Lymphomas

et al. 2021

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“…Scientists at Integral Biosciences have developed a series of potent EZH2 inhibitors that contained an increased fraction of sp 3 carbons to increase the solubility of their inhibitors. 64,65 While keeping the 4,6-dimethylpyridone methyl amide constant, they incorporated a bicyclic nonplanar indoline core in place of the indole and evaluated the effect of substitution at R 1 and R 2 (Table 2). The isopropyl substituted compound (25) was inactive, while the cyclopentyl substituted compound (26) showed a 47-fold improvement in potency.…”

Section: Small Molecules That Inhibit Prc2mentioning

confidence: 99%

Small Molecule Approaches for Targeting the Polycomb Repressive Complex 2 (PRC2) in Cancer

Martin

Zeng

et al. 2020

J. Med. Chem.

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The polycomb repressive complex 2 (PRC2) is composed of three core subunits, enhancer of zeste 2 (EZH2), embryonic ectoderm development (EED), and suppressor of zeste 12 (SUZ12), along with a number of accessory proteins. It is the key enzymatic protein complex that catalyzes histone H3 lysine 27 (H3K27) methylation to mediate epigenetic silencing of target genes. PRC2 thus plays essential roles in maintaining embryonic stem cell identity and in controlling cellular differentiation. Studies in the past decade have reported frequent overexpression or mutation of PRC2 in various cancers including prostate cancer and lymphoma. Aberrant PRC2 function has been extensively studied and proven to contribute to a large number of abnormal cellular processes, including those that lead to uncontrolled proliferation and tumorigenesis. Significant efforts have recently been made to develop small molecules targeting PRC2 function for potential use as anticancer therapeutics. In this review, we describe recent approaches to identify and develop small molecules that target PRC2. These various strategies include the inhibition of the function of individual PRC2 core proteins, the disruption of PRC2 complex formation, and the degradation of its subunits.

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“…To prepare indole derivative 14 , we acylated indole 13 with phenoxyacetyl chloride. Indoline amide 16 was successfully prepared by reduction of indole 13 to obtain N ‐unsubstituted indoline 15 followed by amidation with phenoxyacetic acid.…”

Section: Figurementioning

confidence: 99%

Synthesis and Antibacterial Evaluation of Cephalosporin Isosteres

et al. 2019

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As part of a program to explore the chemistry of β-lactams and their derivatives, we prepared a focused set of benzazetidine, indoline, and indole heterocycles, as well as flexible unconstrained variations of the four-membered heterocyclic compounds. These analogues mimic the threedimensional shape of cephalosporins but are not prone to covalent binding via ring opening. Although these analogues were inactive against the ESKAPE pathogens and Mtb, they represent unique and underexplored chemotypes for future biological screening.

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

Cited by 9 publications

References 20 publications

Discovery of IHMT-EZH2-115 as a Potent and Selective Enhancer of Zeste Homolog 2 (EZH2) Inhibitor for the Treatment of B-Cell Lymphomas

Discovery of IHMT-EZH2-115 as a Potent and Selective Enhancer of Zeste Homolog 2 (EZH2) Inhibitor for the Treatment of B-Cell Lymphomas

Small Molecule Approaches for Targeting the Polycomb Repressive Complex 2 (PRC2) in Cancer

Synthesis and Antibacterial Evaluation of Cephalosporin Isosteres

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