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

Producción científica: Article › revisión exhaustiva

100 Citas (Scopus)

Resumen

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.

Idioma original	English (US)
Número de artículo	6896
Publicación	Nature communications
Volumen	12
N.º	1
DOI	https://doi.org/10.1038/s41467-021-27210-x
Estado	Published - dic 2021
Publicado de forma externa	Sí

ASJC Scopus subject areas

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

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10.1038/s41467-021-27210-x

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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), Artículo 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, n.º 1, 6896. https://doi.org/10.1038/s41467-021-27210-x

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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.",

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AU - Pal, Pratik

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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

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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,

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ASJC Scopus subject areas

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