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…
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,…
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…
My colleagues from The Structural Genomics Consortium (SGC) (Rezart Zhubi, Andreas C. Joerger, Stefan Knapp) just published a paper “๐๐ญ๐ซ๐ฎ๐๐ญ๐ฎ๐ซ๐๐ฅ ๐๐ง๐๐ฅ๐ฒ๐ฌ๐ข๐ฌ ๐จ๐ ๐๐๐๐ ๐๐๐ฆ๐ข๐ฅ๐ฒ ๐๐๐๐๐๐๐ ๐๐จ๐ฆ๐๐ข๐ง๐ฌ ๐๐ง๐ ๐ข๐ญ๐ฌ ๐ข๐ฆ๐ฉ๐ฅ๐ข๐๐๐ญ๐ข๐จ๐ง๐ฌ ๐๐จ๐ซ ๐3-๐ฅ๐ข๐ ๐๐ง๐ ๐๐๐ฌ๐ข๐ ๐ง” that discusses 9 new X-ray structures, providing valuable structural insights for this family of E3 ligases. ๐ Key Structural Findings:โ Conserved ฮฒ-sandwich fold…
Finding potent small-molecule E3 ligase binders is notoriously tough. Hereโs how teams from AstraZeneca, Pharmaron, and XโChem collaborated to overcome this challenge and discover a drugโlike ligand for the CHIP/STUB1 protein. Key highlights ๐ฌ Background and Significance– STUB1/CHIP is a U-box E3 ubiquitin ligase that targets misfolded proteins via interactions with Hsc70/Hsp90.– The currently known…