3800-23-5Relevant articles and documents
Synthesis and characterization of novel isoform-selective IP6K1 inhibitors
Wormald, Michael M.,Ernst, Glen,Wei, Huijun,Barrow, James C.
supporting information, (2019/08/26)
Inositol hexakisphosphate kinases (IP6Ks) have been increasingly studied as therapeutically interesting enzymes. IP6K isoform specific knock-outs have been used to successfully explore inositol pyrophosphate physiology and related pathologies. A pan-IP6K inhibitor, N2-(m-trifluorobenzyl)-N6-(p-nitrobenzyl) purine (TNP), has been used to confirm phenotypes observed in genetic knock-out experiments; however, it suffers by having modest potency and poor solubility making it difficult to handle for in vitro applications in the absence of DMSO. Moreover, TNP's pan-IP6K inhibitory profile does not inform which IP6K isoform is responsible for which phenotypes. In this report we describe a series of purine-based isoform specific IP6K1 inhibitors. The lead compound was identified after multiple rounds of SAR and has been found to selectively inhibit IP6K1 over IP6K2 or IP6K3 using biochemical and biophysical approaches. It also boasts increased solubility and IP6K1 potency over TNP. These new compounds are useful tools for additional assay development and exploration of IP6K1 specific biology.
Purine derivative compounds for medical use
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, (2015/09/22)
The present invention relates to a compound of formula (I): wherein A is N or CH; B is N O, or S; R1 is H, a (C1-C4)alkyl group, a methyl(C1-C6)cycloalkyl group or a (C1-C6)cycloalkyl group; R2 is an aryl, an arylmethyl group or a methylheteroaryl group such as methylpyridine and methylthiophene; R3 is absent when B is O or S, or is H or a (C1-C4)alkyl group when B is N; R4 is a (C1-C5)alkyl group or a (C1-C4)cycloalkyl group, each group bearing a carboxylic acid group, and said (C1-C5)alkyl group or (C1-C4)cycloalkyl being optionally substituted by a hydroxyl group, a halogen group or a methoxy group, and when B is N, R3 and R4 can together form a 5- or 6-membered heterocycle substituted by a carboxylic acid group, and optionally substituted by a halogen atom, a hydroxyl group, a methoxy group or a hydroxymethyl group, or anyone of its pharmaceutically acceptable salt, for use in the treatment of a disease characterized by a reduction in macrophage-mediated bacterial killing. The present invention further relates to a few compounds which are new to the corresponding pharmaceutical composition for the same use.
Design, synthesis and biological evaluation of 6-pyridylmethylaminopurines as CDK inhibitors
Wilson, Stuart C.,Atrash, Butrus,Barlow, Clare,Eccles, Susan,Fischer, Peter M.,Hayes, Angela,Kelland, Lloyd,Jackson, Wayne,Jarman, Michael,Mirza, Amin,Moreno, Javier,Nutley, Bernard P.,Raynaud, Florence I.,Sheldrake, Peter,Walton, Mike,Westwood, Robert,Whittaker, Steven,Workman, Paul,McDonald, Edward
experimental part, p. 6949 - 6965 (2012/01/14)
The cyclin-dependent kinase (CDK) inhibitor seliciclib (1, CYC202) is in phase II clinical development for the treatment of cancer. Here we describe the synthesis of novel purines with greater solubility, lower metabolic clearance, and enhanced potency versus CDKs. These compounds exhibit novel selectivity profiles versus CDK isoforms. Compound αSβR-21 inhibits CDK2/cyclin E with IC50 = 30 nM, CDK7-cyclin H with IC50 = 1.3 μM, and CDK9-cyclinT with IC50 = 0.11 μM; it (CCT68127) inhibits growth of HCT116 colon cancer cells in vitro with GI50 = 0.7 μM; and shows antitumour activity when dosed p.o. at 50 mg/kg to mice bearing HCT116 solid human tumour xenografts.
