TACnology:

TACnology is an emerging term in pharmaceutical science.¹⁾ Modulation of the posttranslational modification (PTM) machinery in nature enables us to control the natural biological process toward the desired direction. PROTAC (PROteolysis TArgeting Chimera) is the most popular TACnology but proteolysis is not the only target for drug design. Chimera molecule-mediated targeting of a particular biological process or chemical events is a clever strategy in pharma especially on cancer-oriented drug discovery programs.²⁾ Targeted protein degradation is a conceptually feasible therapy for cancer and it is a recent paradigm for disease-oriented drug design in terms of mechanism of action.

TACnology is an intensely focused area from basic pharmaceutical research to industrial application and numerous approaches have been developed in the last decade. The underlying concept is to take PTM as a tool for modulation of protein’s fate and functions through enhancement of protein-protein interactions (PPIs) by a bivalent chimeric molecule. Recently posted concepts in TACnology are listed below.

-　PROTAC (PROteolysis TArgeting Chimera)
-　CLIPTAC (CLIck-formed Proteolysis TArgeting Chimera)
-　AUTAC (AUtophagy TArgeting Chimera)
-　LYTAC (Lysosome-TArgeting Chimera)
-　RIBOTAC (RIBOnuclease-TAgeting Chimera)
-　ENTAC (ENhancement-TArgeting Chimera)
-　RIPTAC (Regulated Induced Proximity TArgeting Chimeras)
-　DUBTAC (DeUBiquitinase TArgeting Chimera)
-　DEPTAC (DEPhosphorylation-TArgeting Chimera)
-　PHOTAC (PHOtochemically TArgeting Chimera)
-　PhoRC (Phosphatase-Recruiting Chimera)
-　PhIC (Phosphorylation-Inducing Chimera)
-　AceTAG (Acetylation-TAGging system)
-　TCIP (Transcriptional/epigenetic Chemical Inducers of Proximity)
-　ATTEC (AuTophagosome Tethering Compounds)

According to the UniProt database, more than 450 PTMs are known³⁾ and TACnology can incorporate other biological systems like lysosome and ribonucleases. Thus, these TACnology are just the tip of iceberg.

Target protein degradation (TPD) by PROTAC and the TACnology are attracting attentions especially in oncology and a number of TACs are in clinical trials. Most of the on-going degraders has an engagement with CRBN, a E3 ligase, LYTACs and DUBTACs are also of intensely investigated for drug application so far.

Triggerable TACnology has also been developed for TPD because the molecules of this class can take the proteins in normal cells into degradation that potentially causes the annoying adverse effects. Light-responsible PROTACs⁴⁾ and hypoxia-activated PROTACs⁵⁾ are the representative examples. A trigger by light can activate the molecule in a target organ-specific manner to reduce the side effect on other tissues. Hypoxia is a hallmark of tumor microenvironment and hypoxia-triggered TACs can selectively target cancer cells without external stimuli. CLIPTACs⁶⁾ are also the interesting class of in situ formation of PROTACs by bioorthogonal click chemistry,⁷⁾

TACnology is a novel paradigm of drug discovery and development. Their potential could expand to control of any PTM and there are chances of drug design by a new concept of disease treatment in a molecular level. The potentials of TACnology would keep expansion due to the presence of so many untouched machineries at least at this moment.

Research in academia and industry changed the position of PROTAC since its discovery and report in 2001. It is often the case with a novel technology to take 20 years to mature for practical use. Other TACnology also has potential application in novel drug design and it is worth keeping eyes on the emergence of the related technologies.

1)　https://doi.org/10.3390/molecules28020690
2)　https://doi.org/10.3390/pharmaceutics15102442
3)　https://doi.org/10.1093/nar/gkw1099
4)　https://doi.org/10.1021/acscentsci.9b00713
5)　https://doi.org/10.1039/d1cc05715d
6)　https://doi.org/10.1021/acscentsci.6b00280
7)　https://doi.org/10.1073/pnas.141230798