期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 6, 期 6, 页码 695-700出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.5b00124
关键词
Epigenetics; SMYD2; H3K36; p53; methyltransferase; lysine
资金
- AbbVie [1097737]
- SGC
- Bayer [1097737]
- Boehringer Ingelheim [1097737]
- Genome Canada through Ontario Genomics Institute [OGI- 055]
- GlaxoSmithKline [1097737]
- Janssen [1097737]
- Lilly Canada [1097737]
- Novartis Research Foundation [1097737]
- Ontario Ministry of Economic Development and Innovation [1097737]
- Pfizer [1097737]
- Takeda [1097737]
- Wellcome Trust [1097737, 092809/Z/10/Z]
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.
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