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Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2

Journal Article · · ACS Medicinal Chemistry Letters
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  1. AbbVie, Inc., Chicago, IL (United States)
  2. Univ. of Toronto, ON (Canada)
+ Show Author Affiliations
A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure–activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI ID:
1353263
Journal Information:
ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 6 Vol. 6; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (13)

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A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells journal July 2011
Methylation of the Retinoblastoma Tumor Suppressor by SMYD2 journal September 2010
LLY-507, a Cell-active, Potent, and Selective Inhibitor of Protein-lysine Methyltransferase SMYD2 journal March 2015
The Tale of Two Domains: Proteomics and Genomics Analysis of SMYD2, A New Histone Methyltransferase journal December 2007
Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma journal May 2009

Cited By (13)

Smyd2 conformational changes in response to p53 binding: role of the C‐terminal domain journal May 2019
Inhibitors of Protein Methyltransferases and Demethylases journal March 2017
Histone methyltransferase SMYD2: ubiquitous regulator of disease journal August 2019
Identification of a peptide inhibitor for the histone methyltransferase WHSC1 journal May 2018
Targeting protein methylation: from chemical tools to precision medicines journal May 2019
Histone lysine methyltransferases as anti-cancer targets for drug discovery journal July 2016
Quantitative Profiling of the Activity of Protein Lysine Methyltransferase SMYD2 Using SILAC-Based Proteomics journal January 2016
Epigenetic drug discovery: a success story for cofactor interference journal April 2018
Dysregulation of protein methyltransferases in human cancer: An emerging target class for anticancer therapy journal February 2016
Small molecule inhibitors and CRISPR/Cas9 mutagenesis demonstrate that SMYD2 and SMYD3 activity are dispensable for autonomous cancer cell proliferation journal June 2018
Smyd2 conformational changes in response to p53 binding: role of the C-terminal domain. text January 2019
Methyltransferase Inhibitors: Competing with, or Exploiting the Bound Cofactor journal December 2019
A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion journal October 2019

Figures / Tables (11)

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
Amines
Inhibitors
Monomers
Noncovalent interactions
Peptides and proteins