Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro

Helen A. Paine, Amit Nathubhai, Esther C. Y. Woon, Peter T. Sunderland, Pauline J. Wood, Mary F. Mahon, Matthew D. Lloyd, Andrew S. Thompson, Teemu Haikarainen, Mohit Narwal, Lari Lehtio, Michael D. Threadgill

Research output: Contribution to journalArticle

15 Citations (Scopus)
107 Downloads (Pure)

Abstract

Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD+ as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt / beta-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoisoquinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the Structure-Activity Relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitroisoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethyl¬benzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.
Original languageEnglish
Pages (from-to)5891-5908
Number of pages18
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number17
Early online date2 Jul 2015
DOIs
Publication statusPublished - 1 Sep 2015

Fingerprint

Tankyrases
Benzamides
Deprotonation
Molecular modeling
Niacinamide
beta Catenin
NAD
Adenosine Diphosphate
Tunnels
Crystal structure
Binding Sites
Acids
Substrates
5-aminoisoquinoline
benzonitrile
5-nitroquinoline
1-methylisoquinoline

Cite this

Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro. / Paine, Helen A.; Nathubhai, Amit; Woon, Esther C. Y.; Sunderland, Peter T.; Wood, Pauline J.; Mahon, Mary F.; Lloyd, Matthew D.; Thompson, Andrew S.; Haikarainen, Teemu; Narwal, Mohit; Lehtio, Lari; Threadgill, Michael D.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 17, 01.09.2015, p. 5891-5908.

Research output: Contribution to journalArticle

@article{995d835e422e4811847cfd27aca36381,
title = "Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro",
abstract = "Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD+ as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt / beta-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoisoquinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the Structure-Activity Relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitroisoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethyl¬benzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.",
author = "Paine, {Helen A.} and Amit Nathubhai and Woon, {Esther C. Y.} and Sunderland, {Peter T.} and Wood, {Pauline J.} and Mahon, {Mary F.} and Lloyd, {Matthew D.} and Thompson, {Andrew S.} and Teemu Haikarainen and Mohit Narwal and Lari Lehtio and Threadgill, {Michael D.}",
year = "2015",
month = "9",
day = "1",
doi = "10.1016/j.bmc.2015.06.061",
language = "English",
volume = "23",
pages = "5891--5908",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier",
number = "17",

}

TY - JOUR

T1 - Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro

AU - Paine, Helen A.

AU - Nathubhai, Amit

AU - Woon, Esther C. Y.

AU - Sunderland, Peter T.

AU - Wood, Pauline J.

AU - Mahon, Mary F.

AU - Lloyd, Matthew D.

AU - Thompson, Andrew S.

AU - Haikarainen, Teemu

AU - Narwal, Mohit

AU - Lehtio, Lari

AU - Threadgill, Michael D.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD+ as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt / beta-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoisoquinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the Structure-Activity Relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitroisoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethyl¬benzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.

AB - Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD+ as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt / beta-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoisoquinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the Structure-Activity Relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitroisoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethyl¬benzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.

U2 - 10.1016/j.bmc.2015.06.061

DO - 10.1016/j.bmc.2015.06.061

M3 - Article

VL - 23

SP - 5891

EP - 5908

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 17

ER -