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!

BCCov

“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