Development of structurally novel FMS (CSF-1R) inhibitors for cancer
File(s)
Author(s)
Tangsangasaksri, Kanut
Type
Thesis or dissertation
Abstract
Colony-stimulating factor-1 receptor (CSF-1R) or FMS is a hematopoietic growth factor responsible for cell differentiation, proliferation, and survival. Overexpression of FMS has been implicated in a large number of human pathologies, including inflammatory diseases and several cancers, due to its role in the activation of tumour-associated macrophages (TAMs) which can promote tumour progression and metastasis. Inhibition of FMS can therefore in principle provide therapeutic options for these diseases. In this thesis, we focus on the development of small molecule inhibitors against FMS kinase.
In Chapter 1, we report the design of a novel type of FMS inhibitor, based on promising compounds previously identified in the Fuchter group, and the synthesis of the desired inhibitor and its analogues. Despite significant challenges in the synthesis, the desired inhibitor was successfully synthesised and the routes developed were optimised to synthesise further analogues. Unfortunately, the target inhibitor was found only to be moderately potent against FMS.
In Chapter 2, we report the development of small molecule-based PROTACs (Proteolysis-Targeting Chimeras) which were specifically designed for target protein degradation of FMS. PROTACs have been recently introduced as a novel therapeutic approach since they possess some advantages over other small molecule modalities, including improved selectivity and a catalytic mechanism of action. Our FMS PROTACs were designed based on one of the lead structures presented in Chapter 1. The novel PROTACs were successfully synthesised, and initial biological properties of the synthesised PROTACs were assessed through an in vitro degradation assay. Although the initial biological assay showed that the synthesised PROTACs were not able to degrade FMS, further biological evaluation of the synthesised PROTACs is currently underway.
In Chapter 1, we report the design of a novel type of FMS inhibitor, based on promising compounds previously identified in the Fuchter group, and the synthesis of the desired inhibitor and its analogues. Despite significant challenges in the synthesis, the desired inhibitor was successfully synthesised and the routes developed were optimised to synthesise further analogues. Unfortunately, the target inhibitor was found only to be moderately potent against FMS.
In Chapter 2, we report the development of small molecule-based PROTACs (Proteolysis-Targeting Chimeras) which were specifically designed for target protein degradation of FMS. PROTACs have been recently introduced as a novel therapeutic approach since they possess some advantages over other small molecule modalities, including improved selectivity and a catalytic mechanism of action. Our FMS PROTACs were designed based on one of the lead structures presented in Chapter 1. The novel PROTACs were successfully synthesised, and initial biological properties of the synthesised PROTACs were assessed through an in vitro degradation assay. Although the initial biological assay showed that the synthesised PROTACs were not able to degrade FMS, further biological evaluation of the synthesised PROTACs is currently underway.
Version
Open Access
Date Issued
2021-02
Date Awarded
2021-05
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Fuchter, Matthew
Sponsor
Development and Promotion of Science and Technology Talents Project (DPST)
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)