Comparison of the inhibition of tankyrase-2 by 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones

Michael B C Kenny, Kenneth K Y Cheng, Jack Y C Cheung, Steven K M Fung, Ekaterina Kumpan, Amit Nathubhai, Michael D Threadgill

Research output: Contribution to conferencePoster

Abstract

Tankyrase-1 (PARP-5a, TNKS-1, ARTD5) and tankyrase-2 (PARP-5b, TNKS-2, ARTD6) are members of the poly(ADP-ribose)polymerase (PARP) enzyme superfamily. They currently attract much interest owing to their roles at chromosomal telomeres, at the mitotic spindle and in the wnt signalling pathway, leading to identification as possible targets for drug design for cancer. XAV939 1a, 5-substituted-3-arylisoquinolin-1-ones 2, 2-arylquinazolin-4-ones 3 and 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones 4 have previously been identified as potent and selective inhibitors of the tankyrases.1-4 As part of an exploration of the structure-activity relationship around the core, short series of 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones 1 and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones 5 were synthesised by condensation of the corresponding cyclic beta-keto esters with benzamidines. Both series of compounds inhibited tankyrase-2, although the 7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones 1 were markedly more potent (IC50 8 – 38 nM) than the corresponding 5,6,7,8-tetrahydroquinazolin-4-ones 5 (IC50 172 – 560 nM). A modelling study showed that the two series of compounds bound to the nicotinamide-binding site of the enzyme in conformations with different puckers of the partly saturated rings. Our previous study showed that the tetrahydropyridine ring of 4 does adopt the favoured conformation on binding to tankyrase-2. The inability of the carbocyclic compounds to adopt the optimum conformation of the dihydrothiopyrano analogues upon binding may contribute to their lower potency.

We thank Worldwide Cancer Research (formerly AICR) for part financial support.

Original languageEnglish
Publication statusUnpublished - 2015
Event23rd Conference of the Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A) - Muenster, Germany
Duration: 26 Aug 201527 Aug 2015

Conference

Conference23rd Conference of the Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A)
CountryGermany
CityMuenster
Period26/08/1527/08/15

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Tankyrases
Poly(ADP-ribose) Polymerases
Conformations
Benzamidines
Niacinamide
Enzymes
Condensation
Esters
Binding Sites
Pharmaceutical Preparations

Cite this

Kenny, M. B. C., Cheng, K. K. Y., Cheung, J. Y. C., Fung, S. K. M., Kumpan, E., Nathubhai, A., & Threadgill, M. D. (2015). Comparison of the inhibition of tankyrase-2 by 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones. Poster session presented at 23rd Conference of the Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A), Muenster, Germany.

Comparison of the inhibition of tankyrase-2 by 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones. / Kenny, Michael B C; Cheng, Kenneth K Y; Cheung, Jack Y C; Fung, Steven K M; Kumpan, Ekaterina; Nathubhai, Amit; Threadgill, Michael D.

2015. Poster session presented at 23rd Conference of the Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A), Muenster, Germany.

Research output: Contribution to conferencePoster

Kenny, MBC, Cheng, KKY, Cheung, JYC, Fung, SKM, Kumpan, E, Nathubhai, A & Threadgill, MD 2015, 'Comparison of the inhibition of tankyrase-2 by 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones', 23rd Conference of the Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A), Muenster, Germany, 26/08/15 - 27/08/15.
Kenny MBC, Cheng KKY, Cheung JYC, Fung SKM, Kumpan E, Nathubhai A et al. Comparison of the inhibition of tankyrase-2 by 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones. 2015. Poster session presented at 23rd Conference of the Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A), Muenster, Germany.
Kenny, Michael B C ; Cheng, Kenneth K Y ; Cheung, Jack Y C ; Fung, Steven K M ; Kumpan, Ekaterina ; Nathubhai, Amit ; Threadgill, Michael D. / Comparison of the inhibition of tankyrase-2 by 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones. Poster session presented at 23rd Conference of the Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A), Muenster, Germany.
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title = "Comparison of the inhibition of tankyrase-2 by 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones",
abstract = "Tankyrase-1 (PARP-5a, TNKS-1, ARTD5) and tankyrase-2 (PARP-5b, TNKS-2, ARTD6) are members of the poly(ADP-ribose)polymerase (PARP) enzyme superfamily. They currently attract much interest owing to their roles at chromosomal telomeres, at the mitotic spindle and in the wnt signalling pathway, leading to identification as possible targets for drug design for cancer. XAV939 1a, 5-substituted-3-arylisoquinolin-1-ones 2, 2-arylquinazolin-4-ones 3 and 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones 4 have previously been identified as potent and selective inhibitors of the tankyrases.1-4 As part of an exploration of the structure-activity relationship around the core, short series of 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones 1 and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones 5 were synthesised by condensation of the corresponding cyclic beta-keto esters with benzamidines. Both series of compounds inhibited tankyrase-2, although the 7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones 1 were markedly more potent (IC50 8 – 38 nM) than the corresponding 5,6,7,8-tetrahydroquinazolin-4-ones 5 (IC50 172 – 560 nM). A modelling study showed that the two series of compounds bound to the nicotinamide-binding site of the enzyme in conformations with different puckers of the partly saturated rings. Our previous study showed that the tetrahydropyridine ring of 4 does adopt the favoured conformation on binding to tankyrase-2. The inability of the carbocyclic compounds to adopt the optimum conformation of the dihydrothiopyrano analogues upon binding may contribute to their lower potency.We thank Worldwide Cancer Research (formerly AICR) for part financial support.",
author = "Kenny, {Michael B C} and Cheng, {Kenneth K Y} and Cheung, {Jack Y C} and Fung, {Steven K M} and Ekaterina Kumpan and Amit Nathubhai and Threadgill, {Michael D}",
year = "2015",
language = "English",
note = "23rd Conference of the Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A) ; Conference date: 26-08-2015 Through 27-08-2015",

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TY - CONF

T1 - Comparison of the inhibition of tankyrase-2 by 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones

AU - Kenny, Michael B C

AU - Cheng, Kenneth K Y

AU - Cheung, Jack Y C

AU - Fung, Steven K M

AU - Kumpan, Ekaterina

AU - Nathubhai, Amit

AU - Threadgill, Michael D

PY - 2015

Y1 - 2015

N2 - Tankyrase-1 (PARP-5a, TNKS-1, ARTD5) and tankyrase-2 (PARP-5b, TNKS-2, ARTD6) are members of the poly(ADP-ribose)polymerase (PARP) enzyme superfamily. They currently attract much interest owing to their roles at chromosomal telomeres, at the mitotic spindle and in the wnt signalling pathway, leading to identification as possible targets for drug design for cancer. XAV939 1a, 5-substituted-3-arylisoquinolin-1-ones 2, 2-arylquinazolin-4-ones 3 and 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones 4 have previously been identified as potent and selective inhibitors of the tankyrases.1-4 As part of an exploration of the structure-activity relationship around the core, short series of 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones 1 and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones 5 were synthesised by condensation of the corresponding cyclic beta-keto esters with benzamidines. Both series of compounds inhibited tankyrase-2, although the 7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones 1 were markedly more potent (IC50 8 – 38 nM) than the corresponding 5,6,7,8-tetrahydroquinazolin-4-ones 5 (IC50 172 – 560 nM). A modelling study showed that the two series of compounds bound to the nicotinamide-binding site of the enzyme in conformations with different puckers of the partly saturated rings. Our previous study showed that the tetrahydropyridine ring of 4 does adopt the favoured conformation on binding to tankyrase-2. The inability of the carbocyclic compounds to adopt the optimum conformation of the dihydrothiopyrano analogues upon binding may contribute to their lower potency.We thank Worldwide Cancer Research (formerly AICR) for part financial support.

AB - Tankyrase-1 (PARP-5a, TNKS-1, ARTD5) and tankyrase-2 (PARP-5b, TNKS-2, ARTD6) are members of the poly(ADP-ribose)polymerase (PARP) enzyme superfamily. They currently attract much interest owing to their roles at chromosomal telomeres, at the mitotic spindle and in the wnt signalling pathway, leading to identification as possible targets for drug design for cancer. XAV939 1a, 5-substituted-3-arylisoquinolin-1-ones 2, 2-arylquinazolin-4-ones 3 and 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones 4 have previously been identified as potent and selective inhibitors of the tankyrases.1-4 As part of an exploration of the structure-activity relationship around the core, short series of 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones 1 and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones 5 were synthesised by condensation of the corresponding cyclic beta-keto esters with benzamidines. Both series of compounds inhibited tankyrase-2, although the 7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones 1 were markedly more potent (IC50 8 – 38 nM) than the corresponding 5,6,7,8-tetrahydroquinazolin-4-ones 5 (IC50 172 – 560 nM). A modelling study showed that the two series of compounds bound to the nicotinamide-binding site of the enzyme in conformations with different puckers of the partly saturated rings. Our previous study showed that the tetrahydropyridine ring of 4 does adopt the favoured conformation on binding to tankyrase-2. The inability of the carbocyclic compounds to adopt the optimum conformation of the dihydrothiopyrano analogues upon binding may contribute to their lower potency.We thank Worldwide Cancer Research (formerly AICR) for part financial support.

M3 - Poster

ER -