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

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.