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

ABSTRACT: 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.

SUBMITTER: Sweis RF

PROVIDER: S-EPMC4468393 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Sweis Ramzi F RF Wang Zhi Z Algire Mikkel M Arrowsmith Cheryl H CH Brown Peter J PJ Chiang Gary G GG Guo Jun J Jakob Clarissa G CG Kennedy Steven S Li Fengling F Maag David D Shaw Bailin B Soni Nirupama B NB Vedadi Masoud M Pappano William N WN

ACS medicinal chemistry letters 20150429 6

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 ...[more]

PMID: 26101576

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