Bladder cancer is a common urinary cancer that still lacks effective treatments. In the present study, we evaluated the effect of BET inhibitor, mivebresib, in combination with PZ703b, a Bcl-xl PROTAC, on apoptosis in bladder cancer cells. The results revealed that mivebresib and PZ703b synergistically decreased the viabilities of bladder cancer cells. Co-treatment of mivebresib and PZ703b induced apoptosis in bladder cancer cells via the mitochondrial pathway in a caspase-dependent manner. Mechanistically, mivebresib and PZ703b treatment inhibited the expression of Mcl-1 and Bcl-xl, accompanied by upregulation of Bim. Hence, co-treatment of mivebresib and PZ703b rebalanced the level of pro- and anti-apoptotic Bcl-2 proteins in cells. Further investigations showed that forced expression of Mcl-1 or Bcl-xl markedly protected bladder cancer cells from apoptosis induced by combination treatment of mivebresib and PZ703b. In addition, knockdown of Bim also inhibited the cell death induced by mivebresib/PZ703b in bladder cancer cells. In summary, our findings reveal that the combination treatment of mivebresib and PZ703b represents a novel promising strategy to treat bladder cancer.

14 Oct 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

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

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.

International Journal of Molecular Sciences

A First-in-Class Dual Degrader of Bcl-2/Bcl-xL Reverses HIV Latency and Minimizes Ex Vivo Reservoirs from Patients

Article

Author: Chang, Lin-Chun ; Shah, Jayesh G. ; Yin, Michael T. ; Debnath, Asim K. ; Laird, Gregory M. ; Ritter, Kristen D.

The persistence of latent HIV-1 proviruses in CD4+ T cells is a major obstacle to curing HIV. The “shock and kill” strategy involves reversing latency with latency-reversing agents (LRAs) and selectively inducing cell death in infected cells. However, current LRAs have shown limited efficacy in eliminating the ex vivo HIV reservoir and thus failed in clinical study. In this study, we repurposed PZ703b, a pro-apoptotic protein degrader initially developed for anti-leukemia therapy, to target HIV eradication. PZ703b induced the degradation of Bcl-2 and Bcl-xL, activating the non-canonical NF-kB pathway and caspases cascade, resulting in latency reversal and the selective apoptosis of infected cells. The treatment of ex vivo CD4+ T cells from ART-suppressed HIV-1 patients led to approximately a 50% reduction in the replication-competent reservoir. While this result does not reach the threshold required for a complete cure, it demonstrates the potential of a dual degrader of Bcl-2/Bcl-xL in reversing HIV latency and inducing selective cell death. Our study provides a proof-of-concept for using dual degraders of Bcl-2/Bcl-xL as a novel category of LRAs in therapeutic strategies aimed at reducing HIV reservoirs. This approach may pave the way for the further exploration of targeted interventions to eliminate the HIV-inducible reservoir.

100 Deals associated with PZ703b(University of Florida)

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	University of Florida	17 Sep 2021

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