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

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

  • J Med Chem. 2019 Sep 12;62(17):8152-8163. doi: 10.1021/acs.jmedchem.9b00919.
Ziqian Wang Nianzhe He Zongwei Guo Cuili Niu Ting Song Yafei Guo Keke Cao Anhui Wang Junjie Zhu Xiaodong Zhang Zhichao Zhang
Abstract

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.

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