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

2021; American Chemical Society; Volume: 64; Issue: 19 Linguagem: Inglês

10.1021/acs.jmedchem.1c00517

1520-4804

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

Peptidase Inhibition and Analysis

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.