Every second paper on PROTACs repeats the same phrase that lack of small molecule ligands capable of recruiting various E3 ligases is a major bottleneck for further evolution of TPD field, usually stating that out of 600+ E3 ligases we can recruit only a small fraction (currently around 5%). However, this phrase is becoming a…
Big molecules, big permeability issues. All medicinal chemists know that well. No wonder that many scientists in drug discovery were skeptical whether such large molecules (800+ Da) can make it through clinical trials. Yet they enter cells as well as systemic circulation sufficiently to drive potent target degradation and elicit a therapeutic effect. However, how…
Although PROTACs hijacking cytosolic E3 ligases have been reported to degrade certain trans-membrane (TM) proteins (including EGFR, GPCRs, and PD-L1), It is plausible that this approach is for some TM targets sub-optimal as TM targets have restricted access to the cytosolic degradation machinery. Strategies specifically designed for membrane proteins, such as LYTACs, GlueTACs, and TransTACs,…
Optimization of PROTACs for in vivo applications is non-trivial, thought not impossible. A nice example on this topic represents freshly published paper in J. Med. Chem., showcasing successful optimization of a RIPK1 PROTAC degrader. Previous RIPK1 degrader LD4172 suffered from metabolic degradation and fast clearance (I highlighted the metabolic soft spots in the figure below)….
The field of PROTACs continues to evolve. A recent Nature Communications paper describes another self-assembling nano-PROTAC that co-degrades androgen receptor (AR) and HSP90 and shows promise for treatment of castration-resistant prostate cancer (CRPC). To save your precious time, here is my summary and highlights: Design and mechanismPsa-AR (nano-PROTAC) is a modular peptide comprising:– A PSMA-targeting…
Researchers often steer the design of CRBN-based PROTACs to achieve selective degradation of a single target while suppressing degradation of CRBN neo-substrates. Two different research groups published independently two publications where they approached this differently. By intentional design they developed dual degraders by combining the principles of PROTACs and molecular glue degraders. The first work…
Well, not quite yet. But maybe soon. Frontier Medicines evaluated E3 ligase DCAF2 (DTL/CDT2), as a novel ligase for targeted protein degradation by PROTACs (published in ๐๐ต๐ณ๐ถ๐ค๐ต๐ถ๐ณ๐ฆ): “๐๐ต๐ณ๐ถ๐ค๐ต๐ถ๐ณ๐ข๐ญ ๐ฃ๐ข๐ด๐ช๐ด ๐ง๐ฐ๐ณ ๐๐๐๐2 ๐ข๐ด ๐ข ๐ฏ๐ฐ๐ท๐ฆ๐ญ ๐3 ๐ญ๐ช๐จ๐ข๐ด๐ฆ ๐ง๐ฐ๐ณ ๐๐๐๐๐๐-๐ฎ๐ฆ๐ฅ๐ช๐ข๐ต๐ฆ๐ฅ ๐ต๐ข๐ณ๐จ๐ฆ๐ต๐ฆ๐ฅ ๐ฑ๐ณ๐ฐ๐ต๐ฆ๐ช๐ฏ ๐ฅ๐ฆ๐จ๐ณ๐ข๐ฅ๐ข๐ต๐ช๐ฐ๐ฏ” Why it is importantโ This work addresses a key limitation in PROTAC development: the…
It doesn’t happen very often to see a direct comparison of a molecular glue degrader and PROTAC, as it has been just published in J Med Chem: “๐๐ช๐ด๐ค๐ฐ๐ท๐ฆ๐ณ๐บ ๐ฐ๐ง ๐ข ๐๐ฆ๐ญ๐ฆ๐ค๐ต๐ช๐ท๐ฆ ๐ข๐ฏ๐ฅ ๐๐ฐ๐ต๐ฆ๐ฏ๐ต ๐๐๐6 ๐๐๐๐๐๐ ๐ธ๐ช๐ต๐ฉ ๐๐ง๐ง๐ช๐ค๐ข๐ค๐ช๐ฐ๐ถ๐ด ๐๐ฏ๐ต๐ช๐ฑ๐ณ๐ฐ๐ญ๐ช๐ง๐ฆ๐ณ๐ข๐ต๐ช๐ท๐ฆ ๐๐ค๐ต๐ช๐ท๐ช๐ต๐บ ๐ง๐ฐ๐ณ ๐ต๐ฉ๐ฆ ๐๐ณ๐ฆ๐ข๐ต๐ฎ๐ฆ๐ฏ๐ต ๐ฐ๐ง ๐๐ช๐ง๐ง๐ถ๐ด๐ฆ ๐๐ข๐ณ๐จ๐ฆ ๐โ๐๐ฆ๐ญ๐ญ ๐๐บ๐ฎ๐ฑ๐ฉ๐ฐ๐ฎ๐ข” Why it is interestingโ๏ธ Glue degraders as well…
The microcosmos of biological processes is complex and full of surprises. This is also the case for a new preprint from Richert, Nลฏskovรก et al.ย While developing rabeprazole-thalidomide hybrids as targeted protein degraders, the authors observed rapid, reversible ATP depletion in cells. Surprisingly, this effect was attributed to PROTAC molecules with a certain molecular structure. ๐ ๐ฒ๐ฐ๐ต๐ฎ๐ป๐ถ๐๐บMechanistic…