UNC0224 - CAS 1197196-48-7
Catalog number: 1197196-48-7
Category: Inhibitor
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The methylation of lysine residues on histones plays a central role in determining euchromatin structure and gene expression. The histone methyltransferase (HMTase) G9a can mono- or dimethylate lysine 9 on histone 3 (H3), contributing to early embryogenesis, genomic imprinting, and lymphocyte development. UNC0224 is a potent and selective G9a HMTase inhibitor, exhibiting an IC50 value of 15 nM. Isothermal titration calorimetry revealed UNC0224 binds to G9a with a Kd value of 29 nM. UNC0224 also inhibits GLP, a closely-related H3K9 HMTase, with assay-dependent IC50 values of 20-58 nM, but is more than 1,000-fold selective against SET7/9 (a H3K4 HMTase) and SET8 (a H4K20 HMTase).
UNC0224; UNC-0224; UNC 0224; 7-[3-(Dimethylamino)propoxy]-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-6-methoxy-N-(1-methyl-4-piperidinyl)-4-quinazolinamine
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1.Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines.
Liu F;Chen X;Allali-Hassani A;Quinn AM;Wigle TJ;Wasney GA;Dong A;Senisterra G;Chau I;Siarheyeva A;Norris JL;Kireev DB;Jadhav A;Herold JM;Janzen WP;Arrowsmith CH;Frye SV;Brown PJ;Simeonov A;Vedadi M;Jin J J Med Chem. 2010 Aug 12;53(15):5844-57. doi: 10.1021/jm100478y.
Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth, and the dimethylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a-10 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. On the basis of the structural insights revealed by this cocrystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison K(i) = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date.
2.Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a.
Liu F;Chen X;Allali-Hassani A;Quinn AM;Wasney GA;Dong A;Barsyte D;Kozieradzki I;Senisterra G;Chau I;Siarheyeva A;Kireev DB;Jadhav A;Herold JM;Frye SV;Arrowsmith CH;Brown PJ;Simeonov A;Vedadi M;Jin J J Med Chem. 2009 Dec 24;52(24):7950-3. doi: 10.1021/jm901543m.
SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.
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CAS 1197196-48-7 UNC0224

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