Rational Design of Bioorthogonally Activatable PROTAC for Tumor-Targeted Protein Degradation.

Autor:	Bi T; National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Chunhui Road, Luzhou 646000, China.; Institute of Integrated Chinese and Western Medicine Southwest Medical University, Chunhui Road, Luzhou 646000, China., Liang P; National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Chunhui Road, Luzhou 646000, China.; Institute of Integrated Chinese and Western Medicine Southwest Medical University, Chunhui Road, Luzhou 646000, China., Zhou Y; National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Chunhui Road, Luzhou 646000, China.; Institute of Integrated Chinese and Western Medicine Southwest Medical University, Chunhui Road, Luzhou 646000, China., Wang H; National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Chunhui Road, Luzhou 646000, China.; Institute of Integrated Chinese and Western Medicine Southwest Medical University, Chunhui Road, Luzhou 646000, China., Huang R; National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Chunhui Road, Luzhou 646000, China.; Institute of Integrated Chinese and Western Medicine Southwest Medical University, Chunhui Road, Luzhou 646000, China., Sun Q; National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Chunhui Road, Luzhou 646000, China.; Institute of Integrated Chinese and Western Medicine Southwest Medical University, Chunhui Road, Luzhou 646000, China., Shen H; National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Chunhui Road, Luzhou 646000, China.; Institute of Integrated Chinese and Western Medicine Southwest Medical University, Chunhui Road, Luzhou 646000, China., Yang S; National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Chunhui Road, Luzhou 646000, China.; Institute of Integrated Chinese and Western Medicine Southwest Medical University, Chunhui Road, Luzhou 646000, China., Ren W; National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Chunhui Road, Luzhou 646000, China.; Institute of Integrated Chinese and Western Medicine Southwest Medical University, Chunhui Road, Luzhou 646000, China., Liu Z; National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Chunhui Road, Luzhou 646000, China.; Institute of Integrated Chinese and Western Medicine Southwest Medical University, Chunhui Road, Luzhou 646000, China.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Nov 09; Vol. 66 (21), pp. 14843-14852. Date of Electronic Publication: 2023 Oct 23.
DOI:	10.1021/acs.jmedchem.3c01423
Abstrakt:	Protein degradation mediated by the proteolysis-targeting chimera (PROTAC) has emerged as an efficient strategy to accurately control intracellular protein levels. However, the development of PROTACs is limited by their systemic toxicity. Herein, we report a bioorthogonally activatable prodrug (BT-PROTAC) strategy to accurately control the activity of PROTACs. As a proof of concept, we introduced the highly reactive trans -cyclooctene into PROTAC molecule MZ1, the structure-acitivity relationships of which were well characterized previously, to construct the bioorthogonally activatable prodrug BT-PROTAC. Compared with MZ1, BT-PROTAC is incapable of degradation of BRD4 protein. However, BT-PROTAC can be activated by highly active tetrazine compound BODIPY-TZ in vitro. Furthermore, we could selectively degrade BRD4 protein in tumor tissue enabled by tumor-targeted tetrazine compound IR808-TZ. This strategy may represent an alternative to existing strategies and may be widely applied in the design of BT-PROTAC targeting other proteins.
Databáze:	MEDLINE
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