PROTACs: DESIGN & SYNTHESIS

Proteolysis Targeting Chimeras (PROTACs) are hetero-bifunctional molecules composed of two different ligands, one binding a protein of interest (POI) and the other hijacking an E3 ligase, connected through a linker. By forcing the interaction between the POI and the E3 ligase, PROTACs induce the POI ubiquitylation and thus its successive degradation operated by the proteasome. Since PROTACs are not degraded during the mechanism, this means that a single PROTAC molecule can promote ubiquitylation and degradation of more than one POI equivalent. Indeed, the catalytic and event-driven mechanism of action confers to PROTACs many advantages over traditional protein inhibitors, such as the removal of all the POI functions at once, achievement of a more prolonged biologic effect, reduction of off-target side effects and toxicity, and overcoming drug resistance.Therefore, PROTACs represents an innovative class of compounds that open to a new therapeutic paradigm. Since its first conceptualization in 2001 until now, the interest from both academia and pharma is exponentially growing, with more than 20 PROTACs that have reached clinical investigation so far. In the last 5 years we have devoted a lot of efforts in the rational design and synthesis of PROTACs with anticancer and antiviral activity.

Desantis J, Goracci L. Proteolysis targeting chimeras in antiviral research. Future Med Chem 2022, 14, 459-462.

Desantis J, Mercorelli B, Celegato M, Croci F, Bazzacco A, Baroni M, Siragusa L, Cruciani G, Loregian A, Goracci L. Indomethacin-based PROTACs as pan-coronavirus antiviral agents Eur J Med Chem 2021, 226, 113814.

Lee GT, Nagaya N, Desantis J, Madura J, Sabaawy HE, Kim WJ, Vaz RJ, Cruciani G, Kim IY. Effects of MTX-23, a novel PROTAC of androgen receptor splice variant-7 and androgen receptor, on CRPC resistant to second-line antiandrogen therapy. Mol Cancer Ther 2021, 20, 490-499.

Despite their intriguing potentiality, PROTACs are characterized by a high molecular weight (600–1400 Da), making their delivery and bioavailability the most significant hurdles to overcome on the way to the clinic. Thus, better understanding and prediction of the ADME properties of PROTACs represent an urgent need for their rational design. For this reason, we are also focusing on the investigation of their physicochemical and ADME properties.

Desantis J, Mammoli A, Eleuteri M, Coletti A, Croci F, Macchiarulo A, Goracci L. PROTACs bearing piperazine-containing linkers: what effect on their protonation state? RSC Adv, 2022, 12, 21968-21977.

Goracci L, Desantis J, Valeri A, Castellani B, Eleuteri M, Cruciani G. Understanding the metabolism of Proteolysis Targeting Chimeras (PROTACs): the next step towards pharmaceutical applications. J Med Chem, 2020, 63, 11615-11638.