De novo discovery of a molecular glue-like macrocyclic peptide that induces MCL1 homodimerization.

ABSTRACT: Macrocyclic peptides have emerged as promising drug candidates, filling the gap between small molecules and large biomolecules in drug discovery. The antiapoptotic protein myeloid cell leukemia 1 (MCL1) is crucial for numerous cancers, yet it presents challenges for selective targeting by traditional inhibitors. In this study, we identified a macrocyclic peptide, 5L1, that strongly binds to MCL1, with a dissociation constant (K_D) of 7.1 nM. This peptide shows the potential to specifically inhibit the function of MCL1, and demonstrates effective antitumor activity against several blood tumor cell lines with the half maximal inhibitory concentration (IC₅₀) values for cell-penetrating peptide-conjugated 5L1 in the range of 0.6 to 3 μM. Structural analysis revealed

SUBMITTER: Li F 

PROVIDER: S-EPMC12002256 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature