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|Ref Type||Journal Article|
|Authors||Liu F, Barsyte-Lovejoy D, Li F, Xiong Y, Korboukh V, Huang XP, Allali-Hassani A, Janzen WP, Roth BL, Frye SV, Arrowsmith CH, Brown PJ, Vedadi M, Jin J|
|Title||Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP.|
|Journal||Journal of medicinal chemistry|
|Date||2013 Nov 14|
|Abstract Text||Among epigenetic "writers", "readers", and "erasers", the lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9me2) and nonhistone proteins, have been implicated in a variety of human diseases. A "toolkit" of well-characterized chemical probes will allow biological and disease hypotheses concerning these proteins to be tested in cell-based and animal models with high confidence. We previously discovered potent and selective G9a/GLP inhibitors including the cellular chemical probe UNC0638, which displays an excellent separation of functional potency and cell toxicity. However, this inhibitor is not suitable for animal studies due to its poor pharmacokinetic (PK) properties. Here, we report the discovery of the first G9a and GLP in vivo chemical probe UNC0642, which not only maintains high in vitro and cellular potency, low cell toxicity, and excellent selectivity, but also displays improved in vivo PK properties, making it suitable for animal studies.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|UNC0642||MP-IN-317||EHMT2 Inhibitor 4||UNC0642 (MP-IN-317) is a histone methyltransferase inhibitor that selectively inhibits EHMT2 (G9A) and EHMT1 (GLP), which may result in decreased methylation and potential cytotoxic effects against cancer cells (PMID: 24102134).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||pancreatic carcinoma||not applicable||UNC0642||Preclinical - Cell culture||Actionable||In a preclinical study, a pancreatic carcinoma cell line demonstrated sensitivity to UNC0642, resulting in inhibition of colony formation in culture (PMID: 24102134).||24102134|
|Unknown unknown||breast cancer||not applicable||UNC0642||Preclinical - Cell culture||Actionable||In a preclinical study, UNC0642 decreased H3K9me2 levels, but did not inhibit colony formation in a breast cancer cell line in culture (PMID: 24102134).||24102134|