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Ref Type Journal Article
PMID (31792461)
Authors Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, Liu X, Thummuri D, Yuan Y, Wiegand JS, Pei J, Zhang W, Sharma A, McCurdy CR, Kuruvilla VM, Baran N, Ferrando AA, Kim YM, Rogojina A, Houghton PJ, Huang G, Hromas R, Konopleva M, Zheng G, Zhou D
Title A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity.
Journal Nature medicine
Vol 25
Issue 12
Date 2019 12
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
DT2216 BCL-XL inhibitor 11 DT2216 is a small molecule proteolysis-targeted chimera (PROTAC) that binds to BCL-XL and targets it for degradation, potentially resulting in decreased tumor growth (PMID: 31792461).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown T-cell acute lymphoblastic leukemia not applicable Asparaginase + Dexamethasone + DT2216 + Vincristine Sulfate Preclinical - Pdx Actionable In a preclinical study, the addition of DT2216 to therapy with Oncovin (vincristine), dexamethasone, and Elspar (asparaginase) resulted in increased survival in a chemotherapy-resistant patient-derived xenograft (PDX) model of T-cell acute lymphoblastic leukemia that expressed high levels of BCL2, MCL1, and BCL-XL (BCL2L1) (PMID: 31792461). 31792461
Unknown unknown triple-receptor negative breast cancer not applicable Doxorubicin + DT2216 Preclinical - Cell culture Actionable In a preclinical study, the addition of DT2216 to Adriamycin (doxorubicin) treatment resulted in decreased viability of a triple-negative breast cancer cell line in culture (PMID: 31792461). 31792461
Unknown unknown triple-receptor negative breast cancer not applicable DT2216 + Vincristine Sulfate Preclinical - Cell culture Actionable In a preclinical study, the addition of DT2216 to Oncovin (vincristine) treatment resulted in decreased viability of a triple-negative breast cancer cell line in culture (PMID: 31792461). 31792461
Unknown unknown T-cell acute lymphoblastic leukemia not applicable DT2216 Preclinical - Cell line xenograft Actionable In a preclinical study, DT2216 treatment resulted in decreased BCL-XL expression and increased apoptosis and reduced viability of a T-cell acute lymphoblastic leukemia (T-ALL) cell line in culture, and decreased tumor growth in xenograft models (PMID: 31792461). 31792461
Unknown unknown lung small cell carcinoma not applicable DT2216 + Venetoclax Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of DT2216 and Venclexta (venetoclax) demonstrated synergy in a small cell lung cancer cell line dependent on BCL-XL and BCL-2 for survival, resulting in decreased cell viability in culture, and led to increased tumor growth inhibition in xenograft models with a mean tumor growth inhibition of 98.2% (PMID: 31792461). 31792461
Unknown unknown triple-receptor negative breast cancer not applicable Docetaxel + DT2216 Preclinical - Cell line xenograft Actionable In a preclinical study, the addition of DT2216 to Taxotere (docetaxel) treatment resulted in decreased viability of a triple-negative breast cancer cell line in culture, and resulted in increased tumor growth inhibition in xenograft models compared to either agent alone (PMID: 31792461). 31792461
Unknown unknown multiple myeloma not applicable DT2216 + S63845 Preclinical - Cell culture Actionable In a preclinical study, the combination of DT2216 and S63845 demonstrated synergy in a myeloma cell line dependent on MCL-1 and BCL-XL for survival, resulting in decreased cell viability in culture (PMID: 31792461). 31792461