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

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

(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...

Full description

Saved in:
Bibliographic Details
Published in:Pharmaceutics Vol. 14; no. 12; p. 2829
Main Authors: Sachkova, Anastasia A, Andreeva, Daria V, Tikhomirov, Alexander S, Scherbakov, Alexander M, Salnikova, Diana I, Sorokin, Danila V, Bogdanov, Fedor B, Rysina, Yulia D, Shchekotikhin, Andrey E, Shchegravina, Ekaterina S, Fedorov, Alexey Yu
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 01-12-2022
MDPI
Subjects:
Analysis
Antibodies
Aprotinin
c-Met
cabozantinib
Cancer
Cell culture
Cell growth
Ethylenediaminetetraacetic acid
Growth factors
Investigations
Kinases
Ligands
Ligases
PROTAC
Proteins
Proteolysis
Russia
New York
United States > US
Chicago Illinois
c-Met
cancer
PROTAC
cabozantinib
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:(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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics14122829