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Last update 08 May 2025

TNKS2

Last update 08 May 2025

Basic Info

Synonyms

ADP-ribosyltransferase diphtheria toxin-like 6, ARTD6, PARP-5b

+ [18]

Introduction

Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking (PubMed:11739745, PubMed:11802774, PubMed:19759537, PubMed:21478859, PubMed:23622245, PubMed:25043379). Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation (PubMed:19759537, PubMed:21478859). Also mediates poly-ADP-ribosylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination (PubMed:21478859). Mediates poly-ADP-ribosylation of TERF1, thereby contributing to the regulation of telomere length (PubMed:11739745). Stimulates 26S proteasome activity (PubMed:23622245).

Drugs associated with TNKS2

2X-121

Target

PARP1 x PARP2 x TNKS1 x TNKS2

Mechanism

PARP1 inhibitors [+3]

Active Org.

Allarity Therapeutics, Inc.

Originator Org.

Eisai Co., Ltd.

Active Indication

Ovarian Cancer [+1]

Inactive Indication

Advanced Malignant Solid Neoplasm [+8]

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

RK-582

Target

TNKS1 x TNKS2

Mechanism

TNKS1 inhibitors [+1]

Active Org.

Japanese Foundation for Cancer Research

Originator Org.

Riken Corp.

Active Indication

Metastatic Colorectal Carcinoma [+1]

Inactive Indication

Colonic Cancer

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Basroparib

Target

TNKS1 x TNKS2

Mechanism

TNKS1 inhibitors [+1]

Active Org.

ST Pharm Co., Ltd.

Originator Org.

ST Pharm Co., Ltd.

Active Indication

Advanced Malignant Solid Neoplasm

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with TNKS2

NCT06853496

/ RecruitingPhase 1IIT

Investigator-initiated Phase I Study of a Tankyrase Inhibitor RK-582 for Patients with Unresectable Metastatic Colorectal Cancer

Tankyrase, the fifth and sixth members of the poly(ADP-ribose) polymerase (PARP) family (PARP-5a/b), is responsible for poly(ADP-ribosyl)ation (PARylation), and was originally identified as a factor that promotes the function of telomerase, an enzyme that elongates telomeres. Subsequently, it was reported that tankyrase enhances Wnt/beta-catenin signaling by PARylation and subsequent degradation of AXIN, a negative regulator of Wnt/beta-catenin signaling, suggesting that tankyrase inhibitors may be a new treatment for colorectal cancer.
RK-582 was discovered through lead optimization from a tankyrase inhibitor that suppresses the growth of human colorectal cancer cells. It was confirmed that RK-582 selectively inhibited tankyrase among the PARP family enzymes, suppressed the growth of Wnt/beta-catenin signal-dependent human colorectal cancer cells at both the levels of cultured cells and xenograft tumors in immunodeficient mice, and accumulated AXIN to decrease beta-catenin and downregulate the target gene expression as pharmacodynamic biomarkers.
Based on these findings, RK-582 is thought to have potential as a new treatment for colorectal cancer patients. At present, however, the efficacy and safety of RK-582 in humans have not been confirmed. Thus, this clinical trial is conducted with the aim of investigating the tolerability and safety of RK-582 for patients with unresectable advanced or recurrent colorectal cancer as a first-in-human trial, in which RK-582 is administered to humans for the first time.

Start Date13 Mar 2025

Sponsor / Collaborator

Japanese Foundation for Cancer Research

[+1]

NCT05571969

/ SuspendedPhase 1

A Phase Ib, Open Label, Multicenter Study to Determine the Maximum Tolerated Dose (MTD) of PARPi 2X-121 Monotherapy and the MTD of Dovitinib in Combination With 2X-121 in Patients With Advanced Solid Tumors

This is a Phase Ib, two-part, multi-center study. In Part 1, the study will evaluate the safety and tolerability, antitumor activity, pharmacokinetics, and determine the maximum tolerated dose (MTD) of 2X-121 monotherapy (at BID regimen) in patients with advanced solid tumors. In Part 2, the study will evaluate safety and tolerability, antitumor activity, pharmacokinetics and determine the MTD of dovitinib when given in combination with the MTD of 2X-121 determined in Part 1.

Start Date20 Feb 2023

Sponsor / Collaborator

Allarity Therapeutics, Inc.

[+1]

NCT04505839

/ CompletedPhase 1

First-In-Human Dose-Escalation Study of STP1002 in Patients With Advanced-Stage Solid Tumors

This is an open-label, multicenter, dose-escalation study to evaluate the safety, tolerability, and pharmacokinetics (PK) and to determine the maximum tolerated dose (MTD) of STP1002 in patients with advanced-stage solid tumors.

Start Date30 Jul 2020

Sponsor / Collaborator

ST Pharm Co., Ltd.

[+1]

100 Clinical Results associated with TNKS2

100 Translational Medicine associated with TNKS2

0 Patents (Medical) associated with TNKS2

173

Literatures (Medical) associated with TNKS2

01 Apr 2025·European Journal of Medicinal Chemistry

Substitutions at the C-8 position of quinazolin-4-ones improve the potency of nicotinamide site binding tankyrase inhibitors

Article

Author: Kampasis, Dionysis ; Lehtiö, Lari ; Karelou, Maria ; Waaler, Jo ; Brinch, Shoshy A ; Bosetti, Chiara ; Galera-Prat, Albert ; Kostakis, Ioannis K ; Dhakar, Saurabh S ; Alaviuhkola, Juho

Human diphtheria toxin-like ADP-ribosyltransferases, PARPs and tankyrases, transfer ADP-ribosyl groups to other macromolecules, thereby controlling various signaling events in cells. They are considered promising drug targets, especially in oncology, and a vast number of inhibitors have already been successfully developed. These inhibitors typically occupy the nicotinamide binding site and extend along the NAD⁺ binding groove of the catalytic domain. Quinazolin-4-ones have been explored as compelling scaffolds for such inhibitors and we have identified a new position within the catalytic domain that has not been extensively studied yet. In this study, we investigate larger substituents at the C-8 position and, using X-ray crystallography, we demonstrate that nitro- and diol-substituents engage in new interactions with TNKS2, improving both affinity and selectivity. Both diol- and nitro-substituents exhibit intriguing inhibition of TNKS2, with the diol-based compound EXQ-1e displaying a pIC₅₀ of 7.19, while the nitro-based compound EXQ-2d's pIC₅₀ value is 7.86. Both analogues impact and attenuate the tankyrase-controlled WNT/β-catenin signaling with sub-micromolar IC₅₀. When tested against a wider panel of enzymes, the nitro-based compound EXQ-2d displayed high selectivity towards tankyrases, whereas the diol-based compound EXQ-1e also inhibited other PARPs. Compound EXQ-2d displays in vitro cell growth inhibition of the colon cancer cell line COLO 320DM, while compound EXQ-1e displays nonspecific cell toxicity. Collectively, the results offer new insights for inhibitor development targeting tankyrases and PARPs by focusing on the subsite between a mobile active site loop and the canonical nicotinamide binding site.

01 Mar 2025·Progress in Neuro-Psychopharmacology and Biological Psychiatry

Unraveling the genetic links between depression and type 2 diabetes

Article

Author: Zhang, Fuquan ; Cao, Hongbao ; Chandhoke, Vikas ; Liu, Dongming ; Baranova, Ancha

BACKGROUNDType 2 diabetes (T2D) is a chronic metabolic disorder that has high comorbidity with mental disorders. The genetic relationships between T2D and depression are far from being well understood.METHODSWe performed genetic correlation, polygenic overlap, Mendelian randomization (MR) analyses, cross-trait meta-analysis, and Bayesian colocalization analysis to assess genetic relationships between T2D and depression, in the forms of major depressive disorder (MDD) and depressed affect (DAF). Then, the summary data-based MR (SMR) analysis was performed to prioritize genes contributing to MDD and to T2D from functional perspective. MDD-driven signaling pathways were constructed to understand the influence of MDD on T2D at the molecular level.RESULTST2D has positive genetic correlations both with MDD (r_g = 0.14) and with DAF (r_g = 0.19). The polygenic overlap analysis showed that about 60 % of causal variants for T2D are shared with MDD and DAF. The MR analysis indicated that genetic liabilities to both MDD (OR: 1.24, 95 % CI: 1.11-1.38) and DAF (OR: 1.48, 95 % CI: 1.23-1.78) are associated with an increased risk for T2D, while genetic liability to T2D is not associated with the risk for MDD (OR: 1.00, 95 % CI: 0.99-1.01) or DAF (OR: 1.01, 95 % CI: 1.00-1.02). The cross-trait meta-analysis identified 271 genomic loci, of which 29 were novel. Genetic predisposition to MDD and T2D shares six overlapping loci, involving some well-characterized genes, such as TCF4 and NEGR1. Colocalization analysis revealed three shared chromosome regions between MDD and T2D, which covers mediator genes including SCYL1, DENND1A, and MAD1L1. Molecular pathway analysis suggests mechanisms that promote the development of T2D through inflammatory pathways overactive in patients with MDD. The SMR analysis and the meta-analysis highlighted seven genes with functional implications for both MDD and T2D, including TNKS2, CCDC92, FADS1, ERI1, THUMPD3, NUCKS1, and PM20D1.CONCLUSIONSOur study points out that depression, in the forms of MDD and DAF, may increase the risk of T2D. Analysis of underlying genetic variation and the molecular pathways, connecting depression and T2D, indicate that the pathophysiological foundations of these two conditions have a notable overlap.

01 Feb 2025·Current Pharmaceutical Biotechnology

Exploring the Effects of Chirality of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2- yl)phenyl]imidazolidine-2,4-dione and its Derivatives on the Oncological Target Tankyrase 2. Atomistic Insights

Article

Author: Alahmdi, Mohamed I. ; Salifu, Elliasu. Y. ; Poonan, Preantha ; Abo-Dya, Nader E. ; Soliman, Mahmoud E. S. ; Peters, Xylia Q.

Background:Tankyrases (TNKS) are homomultimers existing in two forms, viz. TNKS1 and TNKS2. TNKS2 plays a pivotal role in carcinogenesis by activating the Wnt//β- catenin pathway. TNKS2 has been identified as a suitable target in oncology due to its crucial role in mediating tumour progression. The discovery of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl) phenyl]imidazolidine-2,4-dione, a hydantoin phenylquinazolinone derivative which exists as a racemic mixture and in its pure enantiomer forms, has reportedly exhibited inhibitory potency towards TNKS2. However, the molecular events surrounding its chirality towards TNKS2 remain unresolved.Methods:Herein, we employed in silico methods such as molecular dynamics simulation coupled with binding free energy estimations to explore the mechanistic activity of the racemic inhibitor and its enantiomer forms on TNKS2 at a molecular level.Results:Favourable binding free energies were noted for all three ligands propelled by electrostatic and van der Waals forces. The positive enantiomer demonstrated the highest total binding free energy (-38.15 kcal/mol), exhibiting a more potent binding affinity to TNKS2. Amino acids PHE1035, ALA1038, and HIS1048; PHE1035, HIS1048 and ILE1039; and TYR1060, SER1033 and ILE1059 were identified as key drivers of TNKS2 inhibition for all three inhibitors, characterized by the contribution of highest residual energies and the formation of crucial high-affinity interactions with the bound inhibitors. Further assessment of chirality by the inhibitors revealed a stabilizing effect of the complex systems of all three inhibitors on the TNKS2 structure. Concerning flexibility and mobility, the racemic inhibitor and negative enantiomer revealed a more rigid structure when bound to TNKS2, which could potentiate biological activity interference. The positive enantiomer, however, displayed much more elasticity and flexibility when bound to TNKS2.Conclusion:Overall, 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione and its derivatives showed their inhibitory prowess when bound to the TNKS2 target via in silico assessment. Thus, results from this study offer insight into chirality and the possibility of adjustments of the enantiomer ratio to promote greater inhibitory results. These results could also offer insight into lead optimization to enhance inhibitory effects.

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TNKS2

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