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Title: 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 (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI ID:
1353263
Journal Information:
ACS Medicinal Chemistry Letters, Vol. 6, Issue 6; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 49 works
Citation information provided by
Web of Science

References (13)

Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma journal May 2009
SMYD2 is highly expressed in pediatric acute lymphoblastic leukemia and constitutes a bad prognostic factor journal April 2014
The Tale of Two Domains: Proteomics and Genomics Analysis of SMYD2, A New Histone Methyltransferase journal December 2007
Methylation of the Retinoblastoma Tumor Suppressor by SMYD2 journal September 2010
Repression of p53 activity by Smyd2-mediated methylation journal November 2006
Biochemical Characterization of Human SET and MYND Domain-Containing Protein 2 Methyltransferase journal July 2011
Structural Basis of Substrate Methylation and Inhibition of SMYD2 journal September 2011
LLY-507, a Cell-active, Potent, and Selective Inhibitor of Protein-lysine Methyltransferase SMYD2 journal March 2015
Small-Molecule Ligands of Methyl-Lysine Binding Proteins journal April 2011
A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells journal July 2011
Discovery and Development of Potent and Selective Inhibitors of Histone Methyltransferase G9a journal January 2014
Discovery of an in Vivo Chemical Probe of the Lysine Methyltransferases G9a and GLP journal October 2013
Substituent Effects on Carbocation Stability:  The p K R for p -Quinone Methide journal July 2003

Cited By (13)

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

Figures / Tables (11)

Figure 1(p. 1)figure Figure 1
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Scheme 1(p. 2)figure Scheme 1
Table 1(p. 2)table Table 1
Scheme 2(p. 3)figure Scheme 2
Scheme 3(p. 3)figure Scheme 3
Table 2(p. 3)table Table 2
Figure 3(p. 4)figure Figure 3
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Figure 6(p. 5)figure Figure 6

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Related Subjects

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