Utilizing PROTAC technology to address the on-_target platelet toxicity associated with inhibition of BCL-XL

Xuan Zhang; Dinesh Thummuri; Yonghan He; Xingui Liu; Peiyi Zhang; Daohong Zhou; Guangrong Zheng

doi:10.1039/C9CC07217A

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Utilizing PROTAC technology to address the on-_target platelet toxicity associated with inhibition of BCL-X_L†

Xuan Zhang,

‡^a Dinesh Thummuri,‡^b Yonghan He,^b Xingui Liu,^b Peiyi Zhang,^a Daohong Zhou^b and Guangrong Zheng

*^a

Author affiliations

* Corresponding authors

^a Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, USA
E-mail: zhengg@cop.ufl.edu

^b Department of Pharmacodynamics, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, USA

Abstract

BCL-X_L, an anti-apoptotic BCL-2 family protein, plays a key role in cancer cell survival. However, the potential of BCL-X_L as an anti-cancer _target has been hampered by the on-_target platelet toxicity because platelets depend on BCL-X_L to maintain their viability. Here we report the development of a PROTAC BCL-X_L degrader, XZ424, which has increased selectivity for BCL-X_L-dependent MOLT-4 cells over human platelets compared with conventional BCL-X_L inhibitors. This proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.

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Article information

DOI: https://doi.org/10.1039/C9CC07217A
Article type: Communication
Submitted: 14 Sep 2019
Accepted: 12 Nov 2019
First published: 19 Nov 2019

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Chem. Commun., 2019,55, 14765-14768

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Utilizing PROTAC technology to address the on-_target platelet toxicity associated with inhibition of BCL-X_L

X. Zhang, D. Thummuri, Y. He, X. Liu, P. Zhang, D. Zhou and G. Zheng, Chem. Commun., 2019, 55, 14765 DOI: 10.1039/C9CC07217A

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