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In recent years, Tankyrases (End Anchor Polymerase, TNKS) has attracted much attention as a new drug target.
more and more drug research on TNKS, showing great prospects for anti-tumor drug development.
Tankyrases, which includes TNKS1 and TNKS2, belongs to the polyadenosine diphosphate keruclease (PARP) family, which includes 17 members, and Tankyrases is one of them.
of the four PARP inhibitors currently approved for the market (Olapali, Lucapali, Nirapali and His Rapali), Olaparib and Niraparib have been shown to have inhibitory effects on TNKS1.
TNKS1 (Tankyrase1/PARP5a) and TNKS2 (Tankyrase2/PARP5b) have two unique domains compared to other members of the PARP family: anchor protein repeat sequence clusters that mediate protein interactions and SAM domains that form omogene or heterogeneum polymers.
existing research confirms that TNKS is involved in a variety of regulations, including filamentation, steady state balance, Wnt signal path, etc.
because of many diseases, especially tumors, inflammatory diseases have to exist Wnt signaling path overactivation, through TNKS regulation of Wnt signaling path is often used as an important direction of drug development.
Figure I Wnt Signal Conduction Pathway (Tankyrase Acting Pathway) (Picture from Reference II) Figure I shows the Wnt Signal Conduction Pathway (Tankyrase Acting Pathway), at normal base levels, Wnt signal transducting is normal, beta-catenin is present in a multi-complex, and the Wnt ligation exists In this case, the Wnt ligation complex interacts with the subjects Frizzled and LRP on the cell surface, facilitating the formation of the Frizzled-Dishevel complex and LRP phosphate through CK1 and GSK3 beta, which in turn promotes the intracellular binding of Axin and LRP, disintegling the degradation complex and releasing beta-catenin into the nucleation.
beta-catenin entering the nucleus of the cell can be combined with the transcription factor family of TCF1/LEF1 to replace transcription inhibitors and activate and promote gene expression of various types of cell proliferation and cell fate.
this process, TNKS can reduce the stability of the degradation complex and increase the level of the Wnt signal by increasing the degradation of Axin.
, in the treatment of tumor diseases, it is generally necessary to suppress the Wnt signal level by inhibiting TNKS, to achieve tumor suppression.
Figure 2 Representative TNKS inhibitors Figure II shows drugs that have been shown to have TNKS inhibitory activity, including the listed drugs Olaparib and Niraparib; The drug is primarily used to suppress tumor cells by participating in DNA defect repair, Merck's Niraparib entered clinical trials in 2008, was officially approved by the FDA in 2017, was approved for listing in Hong Kong, China, in 2018, and was approved for the maintenance of relapsed ovarian cancer in mainland China in 2019.
addition, most of the drugs in the table above can inhibit a variety of PARP family members as pan-inhibitors; WIKI4 and NVP-TNKS656 are TNKS2 selective inhibitors, and MN-64 is TNKS1 selective inhibitors.
So far, there is no specific selective TNKS inhibitors on the market, but with the deepening of research, drug development for TNKS targets is increasing rapidly, many TNKS inhibitors in the development stage also show great potential for clinical application development, look forward to the early market of these drugs, for cancer patients to bring more drug options.
source: 1. Tankyrases/beta-catenin Signaling Pathway as an Anti-a- and Anti-metastatic Target in Hepatocarcinoma Cell Lines, Journal of Cancer, 2020; 2. Structural Basis of Selective Resion of Human Tankyrases, J. Med. Chem., 2012; 3. Effect of Suppressing Tankyrases on Canonical Wnt Pathway: A New Target for The Treatment of Cancer, 2012; 4. Research progress of TNKS as drug target, 2018.
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