Events

Expanding the druggable genome with targeted protein degradation:  the discovery of BMS-986449, a CELMoD^TMdegrader of the transcription factors IKZF2/4

Targeted protein degradation (TPD) enables therapeutic access to disease‑relevant proteins that lack conventional druggable pockets. This presentation describes the discovery of BMS‑986449, a Cereblon E3-Ligase Modulatory Drug (CELMoDTM) molecular glue degrader that selectively targets the transcription factors Helios and EOS (IKZF2/4), key regulators of regulatory T cells (Tregs) in the tumor microenvironment. Structure‑guided medicinal chemistry optimized CELMoD™ isoindolinones to achieve potent IKZF2 degradation with minimal activity against other CRBN neosubstrates. BMS‑986449 shows robust degradation potency and proteome selectivity in primary human Tregs, and a well‑defined CRBN–IKZF2 ternary complex. In human CRBN knock‑in mouse models, robust Helios degradation in tumoral Tregs translates to significant tumor growth inhibition, which is further enhanced in combination with anti‑PD‑1 therapy. Favorable pharmacokinetics, translational PK/PD, and supportive safety data highlight Helios degradation as a promising immuno‑oncology strategy and demonstrates the promise of molecular glue degraders as a modality to expand the druggable genome.

Replacing Atoms in (Hetero)Arenes

Transformations that allow for the replacement of one atom for another in aromatic ring systems will be presented, with emphasis on C-to-N replacements. Key takeaways include the strategies and concepts that enable site-selective replacements without perturbation of the remaining molecular skeleton. Though the chemical modalities employed to accomplish such transformations are diverse, photochemistry and reagent design are a significant focus.
 

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