Discovery of Novel, Thienopyridine-Based Tyrosine Kinase Inhibitors Targeting Tumorigenic RON Splice Variants

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• The tyrosine kinase recepteur d'origine nantais (RON) plays a role in cancer progression.
• Specific splice variants of RON are implicated in tumor development and resistance to therapy.
• Targeting these splice variants presents a potential strategy for novel anticancer drug development.

Purpose of the Study:

• To identify and optimize novel small molecules targeting RON splice variants.
• To evaluate the in vitro and in vivo efficacy of identified compounds as anticancer agents.
• To assess the pharmacokinetic properties and therapeutic potential of lead compounds.

Main Methods:

• Synthesis and structural optimization of thieno[2,3-b]pyridine derivatives.
• In vitro kinase inhibition assays to determine potency against RON splice variants.
• In vitro antiproliferative assays using cancer cell lines.
• In vivo antineoplastic efficacy studies in patient-derived xenograft models.
• Pharmacokinetic profiling of promising drug candidates.

Main Results:

• Thieno[2,3-b]pyridines were identified as potent inhibitors of RON splice variants.
• Compound 15f demonstrated excellent in vitro kinase inhibition and antiproliferative activity.
• Compound 15f exhibited significant in vivo antineoplastic efficacy against tumors expressing RON splice variants.
• In a patient-derived xenograft model, compound 15f showed superior tumor growth inhibition (74.9% at 10 mg/kg) compared to control compounds.
• Compound 15f possessed favorable pharmacokinetic properties.

Conclusions:

• Compound 15f is a potent and selective inhibitor of RON splice variants.
• 15f demonstrates significant preclinical anticancer activity, both in vitro and in vivo.
• 15f exhibits promising therapeutic potential as a novel anticancer agent targeting RON splice variants.