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Author . . 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 the development of anti-tumor drugs.
Tankyrases, which includes TNKS1 and TNKS2, belongs to the poly-adenosine diphosphate keruclease (PARP) family, which includes 17 members, and Tankyrases is one of them.
of the four PARP inhibitors currently approved for sale (Olapali, Reed Kapari, Nirapali and Heraparli), Olaparib and Niraparib have been shown to have a inhibitory effect 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 Action Pathway) (Picture from Reference II) Figure 1 shows the Tankyrase Acting Pathway, where the Wnt signal transductivity is normal at normal base levels, β-catenin exists in a multi-complex, and in the presence of the Wnt ligation 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 causes Axin to bind to the LRP's cytosphere, disintegling the degradation complex and releasing β-catenin into the nucleation.
β-catenin, which enters the nucleus of a cell, can be combined with the transcription factor family of TCF1/LEF1 to replace transcription inhibitors and activate and promote the proliferation of various types of cells and the expression of genes that determine the fate of cells.
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 2 shows drugs that have been shown to have TNKS inhibitors, 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 then approved for maintenance treatment 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, 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/β-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.