| Literature DB >> 34533954 |
Pratik Pal1, Dinesh Thummuri2, Dongwen Lv2, Xingui Liu2, Peiyi Zhang1, Wanyi Hu1, Saikat K Poddar1, Nan Hua2, Sajid Khan2, Yaxia Yuan2, Xuan Zhang1, Daohong Zhou2, Guangrong Zheng1.
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.Entities:
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Year: 2021 PMID： 34533954 PMCID： PMC8900268 DOI： 10.1021/acs.jmedchem.1c00517
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039