Design, Synthesis and In Vitro Investigation of Cabozantinib-Based PROTACs to Target c-Met Kinase

Autor: Anastasia A. Sachkova, Daria V. Andreeva, Alexander S. Tikhomirov, Alexander M. Scherbakov, Diana I. Salnikova, Danila V. Sorokin, Fedor B. Bogdanov, Yulia D. Rysina, Andrey E. Shchekotikhin, Ekaterina S. Shchegravina, Alexey Yu. Fedorov
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Pharmaceutics, Vol 14, Iss 12, p 2829 (2022)
Druh dokumentu: article
ISSN: 1999-4923
DOI: 10.3390/pharmaceutics14122829
Popis: (1) Background: This investigation aimed at developing a series of c-Met-targeting cabozantinib-based PROTACs. (2) Methods: Purification of intermediate and target compounds was performed using column chromatography, in vitro antiproliferation activity was measured using a standard MTT assay and a c-Met degradation assay was performed via the immunoblotting technique. (3) Results: Several compounds exhibited antiproliferative activity towards different cell lines of breast cancer (T47D, MDA-MB-231, SKBR3, HCC1954 and MCF7) at the same level as parent cabozantinib and 7-demethyl cabozantinib. Two target conjugates, bearing a VHL-ligand as an E3-ligase binding moiety and glycol-based linkers, exhibited the effective inhibition of c-Met phosphorylation and an ability to decrease the level of c-Met in HCC1954 cells at micromolar concentrations. (4) Conclusions: Two compounds exhibit c-Met inhibition activity in the nanomolar range and can be considered as PROTAC molecules due to their ability to decrease the total level of c-Met in HCC1954 cells. The structures of the offered compounds can be used as starting points for further evaluation of cabozantinib-based PROTACs.
Databáze: Directory of Open Access Journals
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