What do FDA approved drugs propranolol, naproxen and terbinafine have in common? They all contain a naphthalene moiety, which is a common structural motif in biologically active compounds. The reasons are perhaps clear to most medicinal chemists. Naphthalene fits well into many lipophilic pockets on proteins, many functionalized derivatives of naphthalene are commercially available and…
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…
PROTACs and molecular glue degraders are the front runners in the area of targeted protein degradation (TPD), with several clinical candidates. While they demonstrated their usefulness and applicability on a wide range of proteins with diverse function and structure (many of them being disease relevant or hard-to-drug), probing the intricate mechanisms of biological processes and…
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)….
Top notch medchem building blocks got unlocked. Chemists from Enamine Ltd. published a robust route to saturated azabicyclic scaffolds (Angewandte Chemie): “๐๐ช๐ค๐บ๐ค๐ญ๐ช๐ค ๐๐ด๐ฐ๐ด๐ต๐ฆ๐ณ๐ฆ๐ด ๐ฐ๐ง ๐๐บ๐ณ๐ช๐ฅ๐ช๐ฏ๐ฆ/๐๐ช๐ฑ๐ฆ๐ณ๐ช๐ฅ๐ช๐ฏ๐ฆ: ๐๐ณ๐ฐ๐ฎ ๐๐บ๐ฏ๐ต๐ฉ๐ฆ๐ด๐ช๐ด ๐ต๐ฐ ๐๐ฑ๐ฑ๐ญ๐ช๐ค๐ข๐ต๐ช๐ฐ๐ฏ๐ด” Key innovationKOtBu/Iโ/COโ-mediated cyclizationย of cyclic alkenyl amines, delivering:โ๏ธ 2-azabicyclo[2.2.2]octanes (35-73% yield)โ๏ธ 2-azabicyclo[3.2.1]octaneย (69% yield)โ๏ธ 2-azabicyclo[2.2.1]heptanesย (75-85% yield)โ๏ธ 7-azabicyclo[2.2.1]heptaneย (70% yield)โ๏ธ 2-azabicyclo[3.1.1]heptanesย (62-73% yield)โ๏ธ 2-azabicyclo[2.1.1]hexanesย (52-90% yield) โ 52โ90% yieldโ Scales up to…
๐ธ 50 new CRBN neosubstrates๐ธ 3 bona fide degraders๐ธ 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 highlightsโ Screened 100 CRBN-binders across two cancer cell linesโ Identified 50 novel CRBN neosubstratesโโ …
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…