Scanlon, James J (2022) Design and synthesis of novel non-peptidic KISS1R antagonists to restore drug sensitivity to triple-negative breast cancer patients. (MSc(R) thesis), Kingston University, .
Abstract
Breast cancer (BCa) is the most common neoplasm among women and the leading cause of cancer related mortalities. Globally, basal-like triple-negative breast cancer (TNBC) accounts for approximately 1 in 5 cases of all BCa malignancies but is disproportionally responsible for all BCa associated deaths. The ability of cancer cells to become resistant to chemotherapy continues to be a major obstacle in treating TNBC. KISS1R, a G-protein coupled receptor (GPCR), signals through a plethora of diverse molecular mechanisms that have the potential to regulate the processes navigating TNBC clinical outcomes. Heightened KISS1R signaling promotes chemotherapeutic desensitisation, due to the overexpression of the drug efflux transporter ABCG2 (BCRP).4 Hence, there is an intense interest for the development of novel, synthetic agents, which may synergise with current BCa therapeutic options. Herein, novel compounds designed as small antagonists of KISS1R, with the outlook of restoring drug sensitivity to patients suffering from TNBC are reported. Methodologies for the synthesis of novel pyridine derivatives have been described. The KISS1R antagonistic efficacy for compounds 1 and 2 were evaluated in an outsourced cellular functional assay. Compared to 1, compound 2 exhibited a greater antagonistic effect – thus, 2 presents a potential template for further analogue optimisation and development. Spectroscopic data including high-resolution mass spectra, IR, 1H NMR, in addition to 13C and 2D NMR constitute evidence for the chemical structures for all synthesised compounds. This paper also reports on the preliminary in vitro proliferation assay profile of the peptidic KISS1R antagonists, P-234, in MCF-7 and MDA-MB-231 cell lines. As observed, peptidic antagonists of KISS1R promote cell proliferation in TNBC model cell lines, contrary to PR+/ER+ BCa cell lines.
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