Proteolysis Targeting Chimeras for the Selective Degradation of Mcl-1/Bcl‑2 Derived from Nonselective Target Binding Ligands

Proteolysis
targeting chimera (PROTAC) recruits an E3 ligase to
a target protein to induce its ubiquitination and subsequent degradation.
We reported success in the development of two PROTACs (C3 and C5) that potently and selectively induce the degradation
of Mcl-1 and Bcl-2 (DC50 = 0.7 and 3.0 μM), respectively,
by introducing the E3 ligase cereblon-binding ligand pomalidomide
to Mcl-1/Bcl-2 dual inhibitors S1-6 and Nap-1 with micromolar-range affinity. C3-induced Mcl-1 ubiquitination
translated into much more lethality in Mcl-1-dependent H23 cells than
the most potent Mcl-1 occupancy-based inhibitor A-1210477 with nanomolar-range affinity. Moreover, structure–activity
relationship analysis and molecular dynamic simulations discovered
the structural basis for turning nonselective or promiscuous Bcl-2
family ligands into selective PROTACs. C3 and C5 exhibited reversible depletion in living cells, which provides a
new potent toolkit for gain-of-function studies to probe the dynamic
roles of Bcl-2 and Mcl-1 in apoptosis networks.