Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,

Dongwen Lv; Pratik Pal; Xingui Liu; Yannan Jia; Dinesh Thummuri; Peiyi Zhang; Wanyi Hu; Jing Pei; Qi Zhang; Shuo Zhou; Sajid Khan; Xuan Zhang; Nan Hua; Qingping Yang; Sebastian Arango; Weizhou Zhang; Digant Nayak; Shaun K. Olsen; Susan T. Weintraub; Robert Hromas; Marina Konopleva; Yaxia Yuan; Guangrong Zheng; Daohong Zhou

doi:10.1038/s41467-021-27210-x

Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,

Dongwen Lv, Pratik Pal, Xingui Liu, Yannan Jia, Dinesh Thummuri, Peiyi Zhang, Wanyi Hu, Jing Pei, Qi Zhang, Shuo Zhou, Sajid Khan, Xuan Zhang, Nan Hua, Qingping Yang, Sebastian Arango, Weizhou Zhang, Digant Nayak, Shaun K. Olsen, Susan T. Weintraub, Robert HromasMarina Konopleva, Yaxia Yuan, Guangrong Zheng, Daohong Zhou

Leukemia

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

52 Scopus citations

Abstract

PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRL^VHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.

Original language	English (US)
Article number	6896
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27210-x
State	Published - Dec 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Lv, D., Pal, P., Liu, X., Jia, Y., Thummuri, D., Zhang, P., Hu, W., Pei, J., Zhang, Q., Zhou, S., Khan, S., Zhang, X., Hua, N., Yang, Q., Arango, S., Zhang, W., Nayak, D., Olsen, S. K., Weintraub, S. T., ... Zhou, D. (2021). Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity, Nature communications, 12(1), Article 6896. https://doi.org/10.1038/s41467-021-27210-x

Lv, D, Pal, P, Liu, X, Jia, Y, Thummuri, D, Zhang, P, Hu, W, Pei, J, Zhang, Q, Zhou, S, Khan, S, Zhang, X, Hua, N, Yang, Q, Arango, S, Zhang, W, Nayak, D, Olsen, SK, Weintraub, ST, Hromas, R, Konopleva, M, Yuan, Y, Zheng, G & Zhou, D 2021, 'Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,', Nature communications, vol. 12, no. 1, 6896. https://doi.org/10.1038/s41467-021-27210-x

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title = "Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,",

abstract = "PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.",

author = "Dongwen Lv and Pratik Pal and Xingui Liu and Yannan Jia and Dinesh Thummuri and Peiyi Zhang and Wanyi Hu and Jing Pei and Qi Zhang and Shuo Zhou and Sajid Khan and Xuan Zhang and Nan Hua and Qingping Yang and Sebastian Arango and Weizhou Zhang and Digant Nayak and Olsen, {Shaun K.} and Weintraub, {Susan T.} and Robert Hromas and Marina Konopleva and Yaxia Yuan and Guangrong Zheng and Daohong Zhou",

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AU - Lv, Dongwen

AU - Pal, Pratik

AU - Liu, Xingui

AU - Jia, Yannan

AU - Thummuri, Dinesh

AU - Zhang, Peiyi

AU - Hu, Wanyi

AU - Pei, Jing

AU - Zhang, Qi

AU - Zhou, Shuo

AU - Khan, Sajid

AU - Zhang, Xuan

AU - Hua, Nan

AU - Yang, Qingping

AU - Arango, Sebastian

AU - Zhang, Weizhou

AU - Nayak, Digant

AU - Olsen, Shaun K.

AU - Weintraub, Susan T.

AU - Hromas, Robert

AU - Konopleva, Marina

AU - Yuan, Yaxia

AU - Zheng, Guangrong

AU - Zhou, Daohong

PY - 2021/12

Y1 - 2021/12

N2 - PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.

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Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,

Abstract

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