- Structure-activity relationships of 2-arylquinazolin-4-ones as highly selective and potent inhibitors of the tankyrases
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Tankyrases (TNKSs), members of the PARP (Poly(ADP-ribose)polymerases) superfamily of enzymes, have gained interest as therapeutic drug targets, especially as they are involved in the regulation of Wnt signalling. A series of 2-arylquinazolin-4-ones with varying substituents at the 8-position was synthesised. An 8-methyl group (compared to 8-H, 8-OMe, 8-OH), together with a 4′-hydrophobic or electron-withdrawing group, provided the most potency and selectivity towards TNKSs. Co-crystal structures of selected compounds with TNKS-2 revealed that the protein around the 8-position is more hydrophobic in TNKS-2 compared to PARP-1/2, rationalising the selectivity. The NAD+-binding site contains a hydrophobic cavity which accommodates the 2-aryl group; in TNKS-2, this has a tunnel to the exterior but the cavity is closed in PARP-1. 8-Methyl-2-(4-trifluoromethylphenyl)quinazolin-4-one was identified as a potent and selective inhibitor of TNKSs and Wnt signalling. This compound and analogues could serve as molecular probes to study proliferative signalling and for development of inhibitors of TNKSs as drugs.
- Nathubhai, Amit,Haikarainen, Teemu,Hayward, Penelope C.,Mu?oz-Descalzo, Silvia,Thompson, Andrew S.,Lloyd, Matthew D.,Lehti?, Lari,Threadgill, Michael D.
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supporting information
p. 316 - 327
(2016/05/19)
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- TANKYRASE INHIBITORS
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The present invention relates to a compound of formula I wherein X is C(R6) or N, Y is C or N, and ring A, ring B, R1 and R2 have the meanings defined herein, provided that when ring B is carbocyclic, X is C(R6); or a pharmaceutically acceptable salt or solvate thereof. The compounds are tankyrase-1 and tankyrase-2 inhibitors and are useful in the treatment of a number of conditions, including cancer.
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Page/Page column 116
(2014/06/24)
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- Resistance-modifying agents. 5.1 Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP)
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Clinical studies concerning the role of poly(ADP-ribose) polymerase (PARP) in the repair of drug- and radiation-induced DNA damage have been impeded by the poor solubility, lack of potency, and limited specificity of currently available inhibitors. A seri
- Griffin, Roger J.,Srinivasan, Sheila,Bowman, Karen
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p. 5247 - 5256
(2007/10/03)
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- Benzamide analogs useful as PARP (ADP-ribosyltransferase, ADPRT) DNA repair enzyme inhibitors
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A range of 3-oxybenzamide compounds and related quinazolinone compounds are disclosed which can act as potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase or PARP enzyme (EC 2.4.2.30), and which thereby can provide useful therapeutic compounds for use in conjunction with DNA-damaging cytotoxic drugs or radiotherapy to potentiate the effects of the latter. The compounds disclosed include 3-benzyloxybenzamides, 3-oxybenzamides in which a chain of 5 or more methylene groups terminate in a halogen atom or in a purin-9-yl moiety, certain benzoxazole-4-carboxamide compounds and certain quinazolinone compounds. In formula X and Y together may form a bride -X-Y- that represents the grouping (a), (b) or (c )wherein R5 is H, alkyl, aryl or aralkyl.
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- Novel benzimidazole and quinazolinone inhibitors of the DNA repair enzyme Poly(ADP-ribose)polymerase
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Two novel series of inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase (PARP) were synthesized and evaluated for biological activity. In the benzimidazole-4-carboxamide series, the carbamoyl function was restricted into the putative biologically active conformation via an intramolecular hydrogen bond, while for quinazolin-4-[3H]-ones this was achieved by incorporation of the group into a heterocyclic ring. For both series of compounds, syntheses involved acylation of substituted anthranilic acid derivatives, followed by acid- or base-catalysed cyclization. 8-Hydroxyquinazolin-4-[3H]-ones were prepared from the corresponding 8-methoxy compounds by dealkylation with boron tribromide. PARP inhibitory activity was determined in permeabilized L1210 murine leukaemia cells, in comparison with the established inhibitor 3-hydroxybenzamide (IC50 = 8.3 μM). For both series, inhibitory activity varied with the nature of the 2-substituent, with benzimidazole-4-carboxamides proving approximately tenfold more potent than the previously prepared benzoxazole-4-carboxamides. 2-Arylbenzimidazoles were especially active, and 2-(4-methoxyphenyl)benzimidazole-4-carboxamide (IC50 = 60 nM) is the most potent PARP inhibitor reported to date. In the quinazolinone series, a 2-(4-nitrophenyl) substituent, and either an 8-methyl or 8-hydroxy group conferred potent inhibitory activity, with IC50 values of 0.13 and 0.23 μM, respectively, being observed.
- Griffin,Srinivasan,White,Bowman,Calvert,Curtin,Newell,Golding
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