Design and Synthesis of a Trifunctional Molecular System "Programmed" to Block Epidermal Growth Factor Receptor Tyrosine Kinase, Induce High Levels of DNA Damage, and Inhibit the DNA Repair Enzyme (Poly(ADP-ribose) Polymerase) in Prostate Cancer Cells

• Published in: Journal of medicinal chemistry Vol. 63; no. 11; pp. 5752 - 5762
• Main Authors: Schmitt, Julie, Huang, Shanlong, Goodfellow, Elliot, Williams, Christopher, Jean-Claude, Bertrand J.
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 11.06.2020
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; MULTIFACETED ROLES; HER2; RADIATION; EGFR; CHEMOTHERAPY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b02008

Resistance to chemotherapy in advanced cancers can be mediated by different factors such as epidermal growth factor receptor (EGFR) overexpression and DNA repair enzymes. Therefore, current standards of care usually involve combinations of multiple treatments. Here, to reduce the adverse effects of multiple drug combinations and improve outcome, we proposed a single drug approach to block multiple overlapping effects that characterize chemoresistance. Thus, we designed a new linker that allows assembly of multiple functions (e.g., inhibition of EGFR phosphorylation, induction of DNA lesions, and blockade of their repair) into a single molecule. This led to the successful synthesis of a novel and potent combi-molecule JS230. Here, we demonstrated that in resistant prostate cancer cells overexpressing EGFR, it was capable of (a) inhibiting EGFR in a dose-dependent manner, (b) damaging DNA, and (c) sustaining the damage by inhibiting the DNA repair protein poly(ADP-ribose) polymerase (PARP). The triple mechanism of action of JS230 cumulated into growth inhibitory potency superior to that of classical two- or three-drug combinations.