Discovery of a Novel BCL-XLPROTAC Degrader with Enhanced BCL-2 Inhibition

Pratik Pal, Dinesh Thummuri, Dongwen Lv, Xingui Liu, Peiyi Zhang, Wanyi Hu, Saikat K. Poddar, Nan Hua, Sajid Khan, Yaxia Yuan, Xuan Zhang, Daohong Zhou, Guangrong Zheng

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)14230-14246
Number of pages17
JournalJournal of Medicinal Chemistry
Volume64
Issue number19
DOIs
StatePublished - Oct 14 2021
Externally publishedYes

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine

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