Small-molecule modulators of receptor tyrosine kinases as potential antitumor agents

Abstract

Receptor tyrosine kinases (RTKs) play key roles in signal transduction pathways, thereby affecting many important cellular processes. Dysregulation of RTK activity can cause significant alterations in normal physiological functions, contributing to tumor formation. Therefore, RTKs have become prime targets in cancer therapy. Two main strategies could be adopted to block aberrant RTK activity: i) the use of agents directly interacting with the intracellular kinase domain or ii) the use of agents able to impede the ligand-receptor interaction, by occupying the extracellular ligand-binding site of the receptor. In the present thesis, design and synthesis of two classes of compounds that reflect the two aforementioned strategies of RTK blockage are presented. The first class of compounds consists of irreversible inhibitors directed against the ATP-binding site of EGFR, a validated anticancer drug target. This series of novel EGFR inhibitors was designed with the aim to reduce the high reactivity and, consequently, the off-target toxicity of the traditional irreversible inhibitors, preserving their ability to covalently alkylate a cysteine residue (cys797) of the target. These compounds were obtained combining a 3-aminopropanamide “warhead” with a 4-anilinoquinazoline or a 4-anilinoquinoline-3-carbonitrile driving portion. The second class of compounds consists of small molecules targeting the Eph-ephrin system, which has been found to be involved in oncogenic and angiogenic phenomena. These compounds were prepared starting from lithocholic acid (LCA), recently identified as a competitive and reversible antagonist at the EphA2 receptor. These LCA derivatives interfere with the Eph-ephrin interaction, by recognizing the ephrin-binding domain situated on the extracellular portion of the Eph receptor. In particular, a series of α-amino acid conjugates of LCA was synthesized, achieving potent compounds that could be used as pharmacological tools to further investigate the role of the Eph-ephrin system in cancer.