Nico Cantone

Research Field

Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas

Journal of Medicinal Chemistry (2016)

Rishi G. Vaswani Victor Gehling Les A. Dakin Andrew S. Cook Christopher G. Nasveschuk

Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0.002 μM, cellular EC50 = 0.032 μM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.

PRC2

10.1021/acs.jmedchem.6b01315

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Citations (198)

Supplementary Table S2 from Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers

Patricia J. Keller Elizabeth J. Adams Rentian Wu Alexandre Côté Shilpi Arora

Table with antibody source information including RRID if available

Table (database)

ARID1A

10.1158/0008-5472.26423900

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Supplementary Materials and Methods from Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers

Patricia J. Keller Elizabeth J. Adams Rentian Wu Alexandre Côté Shilpi Arora

Additional method information to describe technical aspects of the experiments described in this manuscript

10.1158/0008-5472.26423906

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Supplementary Table S1 from Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers

Patricia J. Keller Elizabeth J. Adams Rentian Wu Alexandre Côté Shilpi Arora

Table with cell line information including source and RRID

Table (database)

ARID1A

10.1158/0008-5472.26423903.v1

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Supplementary Table S5 from Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers

Patricia J. Keller Elizabeth J. Adams Rentian Wu Alexandre Côté Shilpi Arora

Summary of cell viability data for bladder cancer cells treated with tulmimetostat

ARID1A

10.1158/0008-5472.26423891

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Early Drug‐Discovery Efforts towards the Identification of EP300/CBP Histone Acetyltransferase (HAT) Inhibitors

ChemMedChem (2020)

Annissa J. Huhn A.S. Gardberg Florence Poy François Brucelle Valérie Vivat

Abstract EP300 and CBP (KAT3A/3B) are two highly homologous, multidomain, epigenetic coregulators that play central roles in transcription through the acetylation of lysine residues on histones and other proteins. Both enzymes have been implicated in human diseases, especially cancer. From a high‐throughput screen of 191 000 compounds searching for EP300/CBP histone acetyltransferase (HAT) inhibitors, 18 compounds were characterized by a suite of biochemical enzymatic assays and biophysical methods, including X‐ray crystallography and native mass spectrometry. This work resulted in the discovery of three distinct mechanistic classes of EP300/CBP HAT inhibitors, including two classes not previously described. The profiles of an example of each class of inhibitor are described in detail. A subsequent medicinal chemistry effort led to the development of a novel class of orally bioavailable AcCoA‐competitive EP300/CBP HAT inhibitors with in vivo activity. We believe that this work will prove to be a useful guide for other groups interested in the development of HAT inhibitors.

Histone acetyltransferase

Acetyltransferases

10.1002/cmdc.202000007

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Citations (16)

Risk Stratification for Colon Neoplasia: Screening Strategies Using Colonoscopy and Computerized Tomographic Colonography

Gastroenterology (2006)

Otto S. Lin Richard A. Kozarek Drew Schembre Kamran Ayub Michael Glück

Risk Stratification

Virtual colonoscopy

10.1053/j.gastro.2006.08.015

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