A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity

Sajid Khan; Xuan Zhang; Dongwen Lv; Qi Zhang; Yonghan He; Peiyi Zhang; Xingui Liu; Dinesh Thummuri; Yaxia Yuan; Janet S. Wiegand; Jing Pei; Weizhou Zhang; Abhisheak Sharma; Christopher R. McCurdy; Vinitha M. Kuruvilla; Natalia Baran; Adolfo A. Ferrando; Yong mi Kim; Anna Rogojina; Peter J. Houghton; Guangcun Huang; Robert Hromas; Marina Konopleva; Guangrong Zheng; Daohong Zhou

doi:10.1038/s41591-019-0668-z

A selective BCL-X_L PROTAC degrader achieves safe and potent antitumor activity

Sajid Khan, Xuan Zhang, Dongwen Lv, Qi Zhang, Yonghan He, Peiyi Zhang, Xingui Liu, Dinesh Thummuri, Yaxia Yuan, Janet S. Wiegand, Jing Pei, Weizhou Zhang, Abhisheak Sharma, Christopher R. McCurdy, Vinitha M. Kuruvilla, Natalia Baran, Adolfo A. Ferrando, Yong mi Kim, Anna Rogojina, Peter J. HoughtonGuangcun Huang, Robert Hromas, Marina Konopleva, Guangrong Zheng, Daohong Zhou

Leukemia

Research output: Contribution to journal › Article › peer-review

326 Scopus citations

Abstract

B-cell lymphoma extra large (BCL-X_L) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-X_L inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-X_L proteolysis-targeting chimera (PROTAC), that targets BCL-X_L to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-X_L-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-X_L.

Original language	English (US)
Pages (from-to)	1938-1947
Number of pages	10
Journal	Nature medicine
Volume	25
Issue number	12
DOIs	https://doi.org/10.1038/s41591-019-0668-z
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Khan, S., Zhang, X., Lv, D., Zhang, Q., He, Y., Zhang, P., Liu, X., Thummuri, D., Yuan, Y., Wiegand, J. S., Pei, J., Zhang, W., Sharma, A., McCurdy, C. R., Kuruvilla, V. M., Baran, N., Ferrando, A. A., Kim, Y. M., Rogojina, A., ... Zhou, D. (2019). A selective BCL-X_L PROTAC degrader achieves safe and potent antitumor activity. Nature medicine, 25(12), 1938-1947. https://doi.org/10.1038/s41591-019-0668-z

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 2019, 'A selective BCL-X_L PROTAC degrader achieves safe and potent antitumor activity', Nature medicine, vol. 25, no. 12, pp. 1938-1947. https://doi.org/10.1038/s41591-019-0668-z

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title = "A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity",

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.",

author = "Sajid Khan and Xuan Zhang and Dongwen Lv and Qi Zhang and Yonghan He and Peiyi Zhang and Xingui Liu and Dinesh Thummuri and Yaxia Yuan and Wiegand, {Janet S.} and Jing Pei and Weizhou Zhang and Abhisheak Sharma and McCurdy, {Christopher R.} and Kuruvilla, {Vinitha M.} and Natalia Baran and Ferrando, {Adolfo A.} and Kim, {Yong mi} and Anna Rogojina and Houghton, {Peter J.} and Guangcun Huang and Robert Hromas and Marina Konopleva and Guangrong Zheng and Daohong Zhou",

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AU - Zhang, Qi

AU - He, Yonghan

AU - Zhang, Peiyi

AU - Liu, Xingui

AU - Thummuri, Dinesh

AU - Yuan, Yaxia

AU - Wiegand, Janet S.

AU - Pei, Jing

AU - Zhang, Weizhou

AU - Sharma, Abhisheak

AU - McCurdy, Christopher R.

AU - Kuruvilla, Vinitha M.

AU - Baran, Natalia

AU - Ferrando, Adolfo A.

AU - Kim, Yong mi

AU - Rogojina, Anna

AU - Houghton, Peter J.

AU - Huang, Guangcun

AU - Hromas, Robert

AU - Konopleva, Marina

AU - Zheng, Guangrong

AU - Zhou, Daohong

PY - 2019/12/1

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N2 - 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.

AB - 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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ER -

A selective BCL-X_L PROTAC degrader achieves safe and potent antitumor activity

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