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Published on: November 9, 2020
A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity
Sajid Khan1, Xuan Zhang2, Dongwen Lv1
1Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA.
Abstract:
B-cell lymphoma extra large (BCL-XL) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-XL proteolysis-targeting chimera (PROTAC), that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-XL-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-XL.
Insights
A novel BCL-XL inhibitor, DT2216, uses proteolysis-targeting chimera (PROTAC) technology to degrade cancer-driving BCL-XL proteins. This approach significantly reduces platelet toxicity compared to traditional inhibitors, offering a safer anticancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- B-cell lymphoma extra large (BCL-XL) is a validated cancer target, crucial for tumor cell survival.
- Existing BCL-XL inhibitors like ABT263 cause dose-limiting thrombocytopenia (low platelet count), restricting their clinical use.
- Thrombocytopenia is linked to on-target BCL-XL inhibition in platelets.
Purpose of the Study:
- To develop a novel BCL-XL inhibitor with reduced platelet toxicity.
- To leverage proteolysis-targeting chimera (PROTAC) technology to achieve targeted protein degradation.
- To evaluate the efficacy and safety of the BCL-XL PROTAC, DT2216, in preclinical cancer models.
Main Methods:
- DT2216 was designed as a PROTAC, linking ABT263 to the Von Hippel-Lindau (VHL) E3 ligase.
- In vitro studies assessed DT2216's potency against cancer cell lines and its toxicity to human platelets.
- In vivo studies evaluated DT2216's anti-tumor efficacy in xenograft models, alone and in combination therapy, monitoring for thrombocytopenia.
Main Results:
- DT2216 demonstrated enhanced potency against BCL-XL-dependent cancer cells compared to ABT263.
- DT2216 exhibited significantly lower toxicity to platelets in vitro, attributed to low VHL expression in platelets.
- In vivo, DT2216 effectively suppressed tumor growth without causing significant thrombocytopenia.
Conclusions:
- PROTAC technology can mitigate on-target drug toxicities, rescuing the therapeutic potential of challenging targets like BCL-XL.
- DT2216 represents a promising, first-in-class anticancer agent with a potentially improved safety profile for BCL-XL-targeted therapy.
- Targeted protein degradation offers a viable strategy to overcome limitations of traditional inhibitors in oncology.
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