Open AccessDiscovery of a Novel BCL-XL 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 , cancer research , ubiquitin , apoptosis , pharmacology , 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.