Request Demo

Last update 23 Jan 2025

TNKS2

Last update 23 Jan 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 [+2]

Inactive Indication

B-Cell Lymphoma [+7]

Drug Highest PhasePhase 2

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

TI2-N17

Target

TNKS1 x TNKS2

Mechanism

TNKS1 inhibitors [+1]

Active Org.

Korea Institute of Radiological & Medical Sciences

Originator Org.

Korea Institute of Radiological & Medical Sciences

Active Indication

Colorectal Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with TNKS2

NCT05571969

/ RecruitingPhase 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]

NCT03878849

/ Active, not recruitingPhase 2

Phase II, Prospective Open Label, Single Arm Study to Investigate Anti-tumor Effect and Tolerability of 2X-121 in Patients With Advanced Ovarian Cancer Selected by the 2X-121 DRP®

This study is to be performed as an open label, multicenter, single arm study of 2X-121 to evaluate anti-tumor efficacy of 2X-121 as single agent therapy in a 28-days cycle in advanced ovarian cancer patients. 2X-121 will be supplied for oral administration twice daily as 600 mg (3 x 200 mg) capsules in a 28 days cycle. Patients with predicted high likelihood of responding to the drug (2X-121) using drug response prediction (DRP®), will be included in the study.

Start Date15 Apr 2019

Sponsor / Collaborator

Allarity Therapeutics, Inc.

[+2]

100 Clinical Results associated with TNKS2

100 Translational Medicine associated with TNKS2

0 Patents (Medical) associated with TNKS2

195

Literatures (Medical) associated with TNKS2

01 Feb 2025·Theriogenology

Tankyrase inhibitor IWR-1 modulates HIPPO and Transforming Growth Factor β signaling in primed bovine embryonic stem cells cultured on mouse embryonic fibroblasts

Article

Author: Hu, Peng ; Ju, Zhihua ; Zhang, Yaran ; Huang, Jinming ; Yang, Chunhong ; Zhang, Yan ; Xiao, Yao ; Wang, Yujie ; Wei, Xiaochao ; Gao, Yundong ; Gao, Yaping ; Wang, Xiuge ; Wang, Jinpeng ; Zhang, Minghao ; Jiang, Qiang ; Liu, Wenhao

The use of tankyrase inhibitors is essential for capturing livestock embryonic stem cells (ESC), yet their mechanisms of action remain largely uncharacterized. Previous studies indicate that their roles extend beyond the suppression of canonical WNT signaling. This study investigates the effects of the tankyrase inhibitor IWR-1 on maintaining the pluripotency of bovine embryonic stem cells (bESC) cultured on mitotically inactivated mouse embryonic fibroblasts (MEF). Notably, bESC exhibited significant differentiation after one month of IWR-1 withdrawal, without a clear bias toward any specific germ layer. IWR-1 effectively inhibited TNKS2 activity in bESC, whereas it suppressed TNKS1 protein level in growth-arrested MEF. Early differentiation upon IWR-1 removal induced more substantial transcriptomic changes in MEF than in bESC. Furthermore, cell communication analysis predicted that IWR-1 influenced several paracrine and autocrine signals within the culture system. We also observed that IWR-1 repressed protein abundance of the HIPPO pathway components including TEAD4 and YAP1 in bESC and decreased transcription of HIPPO targeted genes CYR61. Protein analysis in growth-arrested MEF suggested that IWR-1 modulated MEF function by impeding TGF-β1 activation and activin A secretion which mitigated nuclear localization of SMAD2/3 in the bESC. This study underscores the role of tankyrase inhibitors in ESC self-renewal by modulating key signaling pathways and orchestrating cell-cell interactions, which may be meaningful in understanding the delicate signaling control of pluripotency in livestock and improving the culture system.

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.

01 Jan 2025·Journal of Investigative Dermatology

SASH1 S519N Variant Links Skin Hyperpigmentation and Premature Hair Graying to Dysfunction of Melanocyte Lineage

Article

Author: Goldstein, Nathaniel B ; Clements, Christopher M ; Caryotakis, Griffin ; Pacheco, Theresa R ; Zhao, Rui ; Hintzsche, Jennifer ; VanTreeck, Jillian G ; Shellman, Samantha X ; Norris, David A ; Mukherjee, Nabanita ; Vögeli, Beat ; Shellman, Yiqun G ; Tan, Aik-Choon ; Robinson, William A ; Henen, Morkos A ; Wang, Yizhou ; Birlea, Stanca ; Lambert, Karoline A

A better understanding of human melanocyte (MC) and MC stem cell biology is essential for treating MC-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1^S519N variant in a Hispanic family to investigate SASH1 function in the MC lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical examinations, human cell assays, yeast 2-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1^S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. In vitro, we identified SASH1 as a regulator in MC stem cell maintenance and discovered that TNKS2 is crucial for SASH1's role. In addition, the S519N variant is located in one of multiple tankyrase-binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder links both gain and loss of pigmentation in the same individual, hinting to accelerated aging in human MC stem cells. The findings offer insights into the roles of SASH1 and TNKS2 in MC stem cell maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with MC-related disorders should include an assessment and history of hair pigmentation loss.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

TNKS2

Basic Info

Related

Analysis