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

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

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

Author(s) -

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

Publication year - 2021

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/acs.jmedchem.1c00517

Subject(s) - chemistry , bcl xl , ubiquitin ligase , proteolysis , mechanism of action , growth inhibition , cancer research , apoptosis , ubiquitin , biochemistry , in vitro , programmed cell death , biology , enzyme , gene

BCL-X L and BCL-2 are important targets for cancer treatment. BCL-X L specific proteolysis-targeting chimeras (PROTACs) have been developed to circumvent the on-target platelet toxicity associated with BCL-X L inhibition. However, they have minimal effects on cancer cells that are dependent on BCL-2 or both BCL-X L and BCL-2. Here we report a new series of BCL-PROTACs. The lead PZ703b exhibits high potency in inducing BCL-X L 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-X L dependent, BCL-2 dependent, and BCL-X L /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-X L and BCL-2.

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