Medicinal Chemistry

  • Let’s Hijack DCAF2 for TPD?!

    ByAmbrosigen

    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 ๐˜š๐˜ต๐˜ณ๐˜ถ๐˜ค๐˜ต๐˜ถ๐˜ณ๐˜ฆ): “๐˜š๐˜ต๐˜ณ๐˜ถ๐˜ค๐˜ต๐˜ถ๐˜ณ๐˜ข๐˜ญ ๐˜ฃ๐˜ข๐˜ด๐˜ช๐˜ด ๐˜ง๐˜ฐ๐˜ณ ๐˜‹๐˜Š๐˜ˆ๐˜2 ๐˜ข๐˜ด ๐˜ข ๐˜ฏ๐˜ฐ๐˜ท๐˜ฆ๐˜ญ ๐˜Œ3 ๐˜ญ๐˜ช๐˜จ๐˜ข๐˜ด๐˜ฆ ๐˜ง๐˜ฐ๐˜ณ ๐˜—๐˜™๐˜–๐˜›๐˜ˆ๐˜Š-๐˜ฎ๐˜ฆ๐˜ฅ๐˜ช๐˜ข๐˜ต๐˜ฆ๐˜ฅ ๐˜ต๐˜ข๐˜ณ๐˜จ๐˜ฆ๐˜ต๐˜ฆ๐˜ฅ ๐˜ฑ๐˜ณ๐˜ฐ๐˜ต๐˜ฆ๐˜ช๐˜ฏ ๐˜ฅ๐˜ฆ๐˜จ๐˜ณ๐˜ข๐˜ฅ๐˜ข๐˜ต๐˜ช๐˜ฐ๐˜ฏ” Why it is importantโœ… This work addresses a key limitation in PROTAC development: the…

  • PROTAC vs Molecular Glue

    ByAmbrosigen

    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: “๐˜‹๐˜ช๐˜ด๐˜ค๐˜ฐ๐˜ท๐˜ฆ๐˜ณ๐˜บ ๐˜ฐ๐˜ง ๐˜ข ๐˜š๐˜ฆ๐˜ญ๐˜ฆ๐˜ค๐˜ต๐˜ช๐˜ท๐˜ฆ ๐˜ข๐˜ฏ๐˜ฅ ๐˜—๐˜ฐ๐˜ต๐˜ฆ๐˜ฏ๐˜ต ๐˜‰๐˜Š๐˜“6 ๐˜—๐˜™๐˜–๐˜›๐˜ˆ๐˜Š ๐˜ธ๐˜ช๐˜ต๐˜ฉ ๐˜Œ๐˜ง๐˜ง๐˜ช๐˜ค๐˜ข๐˜ค๐˜ช๐˜ฐ๐˜ถ๐˜ด ๐˜ˆ๐˜ฏ๐˜ต๐˜ช๐˜ฑ๐˜ณ๐˜ฐ๐˜ญ๐˜ช๐˜ง๐˜ฆ๐˜ณ๐˜ข๐˜ต๐˜ช๐˜ท๐˜ฆ ๐˜ˆ๐˜ค๐˜ต๐˜ช๐˜ท๐˜ช๐˜ต๐˜บ ๐˜ง๐˜ฐ๐˜ณ ๐˜ต๐˜ฉ๐˜ฆ ๐˜›๐˜ณ๐˜ฆ๐˜ข๐˜ต๐˜ฎ๐˜ฆ๐˜ฏ๐˜ต ๐˜ฐ๐˜ง ๐˜‹๐˜ช๐˜ง๐˜ง๐˜ถ๐˜ด๐˜ฆ ๐˜“๐˜ข๐˜ณ๐˜จ๐˜ฆ ๐˜‰โ€‘๐˜Š๐˜ฆ๐˜ญ๐˜ญ ๐˜“๐˜บ๐˜ฎ๐˜ฑ๐˜ฉ๐˜ฐ๐˜ฎ๐˜ข” Why it is interestingโœ”๏ธ Glue degraders as well…

  • Think spยณ Rich!

    ByAmbrosigen

    Top notch medchem building blocks got unlocked. Chemists from Enamine Ltd. published a robust route to saturated azabicyclic scaffolds (Angewandte Chemie): “๐˜‰๐˜ช๐˜ค๐˜บ๐˜ค๐˜ญ๐˜ช๐˜ค ๐˜๐˜ด๐˜ฐ๐˜ด๐˜ต๐˜ฆ๐˜ณ๐˜ฆ๐˜ด ๐˜ฐ๐˜ง ๐˜—๐˜บ๐˜ณ๐˜ช๐˜ฅ๐˜ช๐˜ฏ๐˜ฆ/๐˜—๐˜ช๐˜ฑ๐˜ฆ๐˜ณ๐˜ช๐˜ฅ๐˜ช๐˜ฏ๐˜ฆ: ๐˜๐˜ณ๐˜ฐ๐˜ฎ ๐˜š๐˜บ๐˜ฏ๐˜ต๐˜ฉ๐˜ฆ๐˜ด๐˜ช๐˜ด ๐˜ต๐˜ฐ ๐˜ˆ๐˜ฑ๐˜ฑ๐˜ญ๐˜ช๐˜ค๐˜ข๐˜ต๐˜ช๐˜ฐ๐˜ฏ๐˜ด” Key innovationKOtBu/Iโ‚‚/COโ‚‚-mediated cyclizationย of cyclic alkenyl amines, delivering:โœ”๏ธ 2-azabicyclo[2.2.2]octanes (35-73% yield)โœ”๏ธ 2-azabicyclo[3.2.1]octaneย (69% yield)โœ”๏ธ 2-azabicyclo[2.2.1]heptanesย (75-85% yield)โœ”๏ธ 7-azabicyclo[2.2.1]heptaneย (70% yield)โœ”๏ธ 2-azabicyclo[3.1.1]heptanesย (62-73% yield)โœ”๏ธ 2-azabicyclo[2.1.1]hexanesย (52-90% yield) โœ… 52โ€“90% yieldโœ… Scales up to…

  • Curious How Drug Discovery Can Be Accelerated by DELโ€‘ML?

    ByAmbrosigen

    Then I would like to invite you to read our paper in RSC Chem. Biol. which also represents my first corresponding authorship: “๐˜‹๐˜ช๐˜ด๐˜ค๐˜ฐ๐˜ท๐˜ฆ๐˜ณ๐˜บ ๐˜ฐ๐˜ง ๐˜ข๐˜ฏ ๐˜ฆ๐˜น๐˜ฒ๐˜ถ๐˜ช๐˜ด๐˜ช๐˜ต๐˜ฆ๐˜ญ๐˜บ ๐˜ด๐˜ฆ๐˜ญ๐˜ฆ๐˜ค๐˜ต๐˜ช๐˜ท๐˜ฆ ๐˜ž๐˜‹๐˜™5 ๐˜ค๐˜ฉ๐˜ฆ๐˜ฎ๐˜ช๐˜ค๐˜ข๐˜ญ ๐˜ฑ๐˜ณ๐˜ฐ๐˜ฃ๐˜ฆ ๐˜ข๐˜ค๐˜ค๐˜ฆ๐˜ญ๐˜ฆ๐˜ณ๐˜ข๐˜ต๐˜ฆ๐˜ฅ ๐˜ฃ๐˜บ ๐˜ข ๐˜ฉ๐˜ช๐˜จ๐˜ฉ-๐˜ฒ๐˜ถ๐˜ข๐˜ญ๐˜ช๐˜ต๐˜บ ๐˜‹๐˜Œ๐˜“โ€“๐˜”๐˜“ ๐˜๐˜ช๐˜ต” (DEL-ML = DNA Encoded Library + Machine Learning) Highlightsโœ… We demonstrate power of DEL-ML and how it can accelerate…

  • Drugging the “Undruggable” ๐Ÿ’Š

    ByAmbrosigen

    ๐Ÿ”ธ 50 new CRBN neosubstrates๐Ÿ”ธ 3 bona fide degraders๐Ÿ”ธ MS-proteomic platform expanding druggable proteome All of this packed in single paperโ— by colleagues from NEOsphere Biotechnologies GmbH, ICR Centre for Protein Degradation and St. Jude Children’s Research Hospital – ALSAC Additional highlightsโœ… Screened 100 CRBN-binders across two cancer cell linesโœ… Identified 50 novel CRBN neosubstratesโ—โœ……

  • Nine New TRIM PRYSPRY Structures Uncover Key Drug Design Challenges

    ByAmbrosigen

    My colleagues from The Structural Genomics Consortium (SGC) (Rezart Zhubi, Andreas C. Joerger, Stefan Knapp) just published a paper “๐’๐ญ๐ซ๐ฎ๐œ๐ญ๐ฎ๐ซ๐š๐ฅ ๐š๐ง๐š๐ฅ๐ฒ๐ฌ๐ข๐ฌ ๐จ๐Ÿ ๐“๐‘๐ˆ๐Œ ๐Ÿ๐š๐ฆ๐ข๐ฅ๐ฒ ๐๐‘๐˜๐’๐๐‘๐˜ ๐๐จ๐ฆ๐š๐ข๐ง๐ฌ ๐š๐ง๐ ๐ข๐ญ๐ฌ ๐ข๐ฆ๐ฉ๐ฅ๐ข๐œ๐š๐ญ๐ข๐จ๐ง๐ฌ ๐Ÿ๐จ๐ซ ๐„3-๐ฅ๐ข๐ ๐š๐ง๐ ๐๐ž๐ฌ๐ข๐ ๐ง” that discusses 9 new X-ray structures, providing valuable structural insights for this family of E3 ligases. ๐Ÿ”‘ Key Structural Findings:โœ… Conserved ฮฒ-sandwich fold…

  • Discovery of Small-Molecule Ligands for the E3 Ligase STUB1/CHIP

    ByAmbrosigen

    Finding potent small-molecule E3 ligase binders is notoriously tough. Hereโ€™s how teams from AstraZeneca, Pharmaron, and Xโ€‘Chem collaborated to overcome this challenge and discover a drugโ€‘like ligand for the CHIP/STUB1 protein. Key highlights ๐Ÿ”ฌ Background and Significance– STUB1/CHIP is a U-box E3 ubiquitin ligase that targets misfolded proteins via interactions with Hsc70/Hsp90.– The currently known…

  • From serendipity to essential protac profiling

    ByAmbrosigen

    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— ๐—ฒ๐—ฐ๐—ต๐—ฎ๐—ป๐—ถ๐˜€๐—บMechanistic…