Discovery of a Novel BCL-XL PROTAC Degrader with Enhanced BCL-2 Inhibition

  • J Med Chem. 2021 Oct 14;64(19):14230-14246. doi: 10.1021/acs.jmedchem.1c00517.
Pratik Pal  1 ,  Dinesh Thummuri  2 ,  Dongwen Lv  2 ,  Xingui Liu  2 ,  Peiyi Zhang  1 ,  Wanyi Hu  1 ,  Saikat K Poddar  1 ,  Nan Hua  2 ,  Sajid Khan  2 ,  Yaxia Yuan  2 ,  Xuan Zhang  1 ,  Daohong Zhou  2 ,  Guangrong Zheng  1
Affiliations
  • 1. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, Florida 32610, United States.
  • 2. Department of Pharmacodynamics, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, Florida 32610, United States.
PMID: 34533954 DOI: 10.1021/acs.jmedchem.1c00517
Abstract

BCL-XL and Bcl-2 are important targets for Cancer treatment. BCL-XL specific proteolysis-targeting chimeras (PROTACs) have been developed to circumvent the on-target platelet toxicity associated with BCL-XL inhibition. However, they have minimal effects on Cancer cells that are dependent on Bcl-2 or both BCL-XL and Bcl-2. Here we report a new series of BCL-PROTACs. The lead PZ703b exhibits high potency in inducing BCL-XL degradation and in inhibiting but not degrading Bcl-2, showing a hybrid dual-targeting mechanism of action that is unprecedented in a PROTAC molecule. As a result, PZ703b is highly potent in killing BCL-XL dependent, Bcl-2 dependent, and BCL-XL/Bcl-2 dual-dependent cells in an E3 Ligase (VHL)-dependent fashion. We further found that PZ703b forms stable {BCL-2:PROTAC:VCB} ternary complexes in live cells that likely contribute to the enhanced Bcl-2 inhibition by PZ703b. With further optimization, analogues of PZ703b could potentially be developed as effective antitumor agents by co-targeting BCL-XL and Bcl-2.

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