Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases - PubMed (original) (raw)

. 2013 Oct 15;4(12):1173-7.

doi: 10.1021/ml400260b. eCollection 2013 Dec 12.

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Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases

Amit Nathubhai et al. ACS Med Chem Lett. 2013.

Abstract

Tankyrases (TNKSs) are poly(ADP-ribose)polymerases (PARPs) that are overexpressed in several clinical cancers. They regulate elongation of telomeres, regulate the Wnt system, and are essential for the function of the mitotic spindle. A set of 2-arylquinazolin-4-ones has been designed and identified as potent and selective TNKS inhibitors, some being more potent and selective than the lead inhibitor XAV939, with IC50 = 3 nM vs. TNKS-2. Methyl was preferred at the 8-position and modest bulk at the 4-position of the 2-phenyl group; electronic effects and H-bonding were irrelevant, but charge in the 4'-substituent must be avoided. Molecular modeling facilitated initial design of the compounds and rationalization of the SAR of binding into the nicotinamide-binding site of the target enzymes. These compounds have potential for further development into anticancer drugs.

Keywords: PARP; Tankyrase; hydrophobic pocket; quinazolin-4-one; selectivity.

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Figures

Figure 1

Figure 1

Structure of XAV939 1 and representation of the X-ray crystal structure of 1 bound into the NAD+-binding catalytic domain of human tankyrase-2. Key protein residues are in gray, and key H-bond interactions are shown as green dashed lines.

Scheme 1

Scheme 1. Syntheses of Target 2-Arylquinazolin-4-ones 3, 7, and 11 and Locant Numbers

Reagents and conditions: i, PhCHO, NaHSO3, AcNMe2, 150 °C, open flask; ii, CDI; iii, aq. NH3; iv, ArCOCl, pyridine; v, aq. NaOH (0.5 M), 60°C; vi, +NH4HCO2–, Pd/C, MeOH, DMF; vii, BBr3, CH2Cl2 reflux; viii, CbzCl, aq. K2CO3; ix, SOCl2; x, 5a, pyridine; xi, aq. K2CO3 (1.0 M), 100°C; xii, HBr, AcOH.

Figure 2

Figure 2

Molecular modeling of 2-arylquinazolin-4-one inhibitors into the structure of the nicotinamide-binding site of tankyrase-2. The upper four panels compare the binding of the 8-substituent while keeping the 2-aryl group constant. The lower five panels show the location of the 2-aryl group in the hydrophobic pocket, placing the 4′-substituent in a narrower tunnel through to solvent water.

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