Macrocyclic DELs enable rapid, systematic exploration of beyond-Ro5 chemical space that is challenging to access efficiently with peptide or mRNA display. We describe a platform that yielded low-nanomolar, highly selective inhibitors of Bcl-2 family proteins and revealed structural principles governing potency and selectivity. We also highlight lessons learned and strategies for designing next-generation macrocyclic DELMacrocyclic DELs enable rapid, systematic exploration of beyond-Ro5 chemical space that is challenging to access efficiently with peptide or mRNA display. We describe a platform that yielded low-nanomolar, highly selective inhibitors of Bcl-2 family proteins and revealed structural principles governing potency and selectivity. We also highlight lessons learned and strategies for designing next-generation macrocyclic DELs.

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