Tankyrase inhibitors as antitumor agents: a patent update (2013 – 2020)

Mehta, Chirag C.; Bhatt, Hardik

doi:10.1080/13543776.2021.1888929

Cited by 15 publications

(13 citation statements)

References 61 publications

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“…Elevated expression of YAP has been identified in various human cancers, and as YAP inhibitor development is very limited, TNKS inhibition could be a valid alternative for hampering YAP oncogenic properties . Several TNKS inhibitors have been developed , such as compounds E7449 and STP1002 (structure undisclosed), which have progressed in clinical studies, even if compound E7449 behaves as a dual TNKS1–2 and PARP1–2 inhibitor. Other TNKS inhibitors such as RK287107 ( 1 ) and OM-153 ( 2 ) are being evaluated in preclinical studies.…”

Section: Introductionmentioning

confidence: 99%

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Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

et al. 2022

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Major advances have recently defined functions for human mono-ADP-ribosylating PARP enzymes (mono-ARTs), also opening up potential applications for targeting them to treat diseases. Structural biology combined with medicinal chemistry has allowed the design of potent small molecule inhibitors which typically bind to the catalytic domain. Most of these inhibitors are at the early stages, but some have already a suitable profile to be used as chemical tools. One compound targeting PARP7 has even progressed to clinical trials. In this review, we collect inhibitors of mono-ARTs with a typical “H–Y−Φ” motif (Φ = hydrophobic residue) and focus on compounds that have been reported as active against one or a restricted number of enzymes. We discuss them from a medicinal chemistry point of view and include an analysis of the available crystal structures, allowing us to craft a pharmacophore model that lays the foundation for obtaining new potent and more specific inhibitors.

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Section: Introductionmentioning

confidence: 99%

“…While the development of poly-ART inhibitors is widely pursued with new compounds continuing to appear in the literature, ,,− the mono-ART inhibitor development is still in the early stages. However, remarkable advances have been achieved during recent years.…”

Section: Introductionmentioning

confidence: 99%

Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

et al. 2022

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“…The latter binding mode results in a lower selectivity across the PARP family. Other compounds target both pockets in the catalytic domain. ,− Inhibitors based on the 1,2,4-triazole scaffold such as JW74, G007-LK, OD336, and OM-1700 ( 1 ) target the adenosine binding pocket of the TNKS1/2 catalytic domain with high selectivity and are therefore able to display selectivity over other members of the PARP family.…”

Section: Introductionmentioning

confidence: 99%

Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II

et al. 2021

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Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modification by poly-ADP-ribosylation of a plethora of target proteins. In this function, TNKS1/2 also impact the WNT/β-catenin and Hippo signaling pathways that are involved in numerous human disease conditions including cancer. Targeting TNKS1/2 with small-molecule inhibitors shows promising potential to modulate the involved pathways, thereby potentiating disease intervention. Based on our 1,2,4-triazole-based lead compound 1 (OM-1700), further structure–activity relationship analyses of East-, South- and West-single-point alterations and hybrids identified compound 24 (OM-153). Compound 24 showed picomolar IC 50 inhibition in a cellular (HEK293) WNT/β-catenin signaling reporter assay, no off-target liabilities, overall favorable absorption, distribution, metabolism, and excretion (ADME) properties, and an improved pharmacokinetic profile in mice. Moreover, treatment with compound 24 induced dose-dependent biomarker engagement and reduced cell growth in the colon cancer cell line COLO 320DM.

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“…Subsequent biochemical and structural analyses described later suggested that the C-3 functionalization of the triazole ring could improve selectivity. Indeed, additional compounds were prepared by placing a heteroatom, oxygen, sulfur or nitrogen in this position, which was also derivatized while maintaining a 7-methyl (19)(20)(21)(22)(23)(24)(25) or a 5,8-dimethoxy (26)(27)(28)(29)(30)(31) substitution pattern in the benzene ring (Table 3).…”

Section: Biochemical Analysis and Structural Studies Of Oul40 (1) And...mentioning

confidence: 99%

[1,2,4]Triazolo[3,4-b]benzothiazole scaffold as versatile nicotinamide mimic allowing nanomolar inhibition of different PARP enzymes

Murthy

Nizi

Maksimainen

et al. 2022

Preprint

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Here we report [1,2,4]triazolo[3,4-b]benzothiazole (TBT) as a new inhibitor scaffold, which competes with nicotinamide in the binding pocket of human poly- and mono-ADP-ribosylating enzymes. The binding mode was studied through analogs and their crystal structures with TNKS2, PARP2, PARP14 and PARP15. Based on the substitution pattern, we were able to identify The 3-amino derivatives 21 (OUL243) and 27 (OUL232), as inhibitors of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14 and PARP15 at nM potencies, with compound 27 being the most potent PARP10 inhibitor described to date with an IC50 of 7.8 nM and the first PARP12 inhibitor ever reported. On the contrary, hydroxy derivative 16 (OUL245) inhibits poly-ARTs with a selectivity towards PARP2. The scaffold does not possess inherent cell toxicity and the inhibitors can enter cells and engage with the target protein. This, together with favorable ADME properties, demonstrates the potential of the TBT scaffold for future drug development efforts towards selective inhibitors against specific enzymes.

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Tankyrase inhibitors as antitumor agents: a patent update (2013 – 2020)

Cited by 15 publications

References 61 publications

Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II

[1,2,4]Triazolo[3,4-b]benzothiazole scaffold as versatile nicotinamide mimic allowing nanomolar inhibition of different PARP enzymes

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