Targeted protein degrader development for cancer: advances, challenges, and opportunities

Diverse drug delivery systems for the enhancement of cancer immunotherapy: an overview

“…Although drug development using PROTACs and their derived technologies is very promising and offer new therapeutic avenues for tumor immunotherapy, there are still many challenges to clinical application ( 209 ). Apart from the challenges of developing small molecule E3 ligase ligands, developed PROTACs molecules suffer from off-targeting, poor cell permeability, poor cell and tissue selectivity, poor stability, and significant molecular weight ( 210 – 213 ).…”

Small Molecule Inhibitors Targeting the “Undruggable” Survivin: The Past, Present, and Future from a Medicinal Chemist’s Perspective

“…The approach in inhibiting survivin homodimerization leading to its degradation is interesting considering that the strategy in targeted protein degradation (TPD) including the technology of proteolysis-targeting chimeras (PROTAC) 206,207 and molecular-glues 208 are gaining rapid traction with nearly 50 TPD agents currently undergoing clinical evaluation. 206,207 It is noteworthy that the advantage of the compounds 7−9 in targeting the homodimerization interface to induce survivin degradation is that it does not require any moiety to recruit E3 ligase to initiate proteasome-dependent degradation of survivin. Future studies in this direction are warranted to selectively induce degradation of homodimeric target proteins in general and inhibit survivin protein specifically for further development.…”

“…While targeting survivin transcription was initially thought to be appropriate if its promoter DNA sequence could be selectively targeted since survivin was considered “undruggable”, recent successes in targeting survivin dimerization or its interaction with its binding partners suggest that it is possible to develop inhibitors targeting the survivin protein directly. The approach in inhibiting survivin homodimerization leading to its degradation is interesting considering that the strategy in targeted protein degradation (TPD) including the technology of proteolysis-targeting chimeras (PROTAC) , and molecular-glues are gaining rapid traction with nearly 50 TPD agents currently undergoing clinical evaluation. , It is noteworthy that the advantage of the compounds 7 – 9 in targeting the homodimerization interface to induce survivin degradation is that it does not require any moiety to recruit E3 ligase to initiate proteasome-dependent degradation of survivin. Future studies in this direction are warranted to selectively induce degradation of homodimeric target proteins in general and inhibit survivin protein specifically for further development.…”

“…PROTAC or molecular glues act by hijacking a ubiquitin E3 ligase to mediate targeted protein degradation . These molecules have considerable potential to eliminate “undruggable” protein targets such as survivin. , Many promising molecules generated using the PROTAC technology have been developed with about 50 currently in clinical trials. ,,− Given the availability of survivin-targeting small molecules, including 4 and 7 to 9 , such a PROTAC targeting survivin is not out of reach in the near future.…”

Recent advancements in targeted protein knockdown technologies—emerging paradigms for targeted therapy

“…PROTACs are a class of molecules that allow direct protein knockdown via the proteasomal degradation pathway. While traditional targeted drugs require strong binding affinity for the target protein, agents such as PROTACs can label a target protein through weak binding, thus offering a potential solution for 80% of the “undruggable” targets [ 12 , 13 ]. PROTACs are hetero-bifunctional molecules that contain two ligands connected by a linker: one for recruitment and binding to the target protein, and the other for recruitment and binding to E3 ubiquitin ligase ( Figure 1 ).…”