Drug Hunter Journal Club: March 2023

There were plenty of scientific highlights from the literature that we didn’t have space for in Molecules of the Month – here’s a reader’s digest rounding up ~20 molecules of potential interest that we didn’t have space to highlight, including Pfizer’s covalent heterobifunctional BTK degrader, BMS’ brain-penetrant GSK-3β inhibitor, the discovery story of futibatinib from Taiho, and more snippets to jumpstart your reading!


covalent heterobifunctional BTK degrader
WT BTKFL DC50 = 57 nM, WT BTKFL-C481S DC50 = 122 nM

“A covalent BTK ternary complex compatible with targeted protein degradation” 
Nat. Comm., March 02, 2023 
DOI link: https://doi.org/10.1038/s41467-023-36738-z 

  • Proof-of-concept: covalent target recruitment is compatible with targeted protein degradation
    • A BTK-binder based on ibrutinib was fused with a known IAP-family of E3 ligase recruiters through the acrylamide covalent warhead
    • Both non-covalent and covalent versions of the degrader had similar DC50 values
    • SPR, NMR, multi-angle light scattering, and chemical crosslinking confirmed that BTK~BCCov forms a stable ternary complex with cIAP1
  • Why we care: 
    • Covalent ligands could be used in the future as components of degraders targeting non-enzymatic proteins
    • Libraries of covalent modifiers might be quickly prepared in the future through acrylamides linked to E3-ligase recruiters
    • Reversible covalent ligands might also be catalytically competent in the future

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