A Comprehensive Monograph on Tivantinib (ARQ-197): From a Promising c-MET Inhibitor to a Discontinued Antineoplastic Agent

Executive Summary

Tivantinib, also known by its development code ARQ-197, is an orally bioavailable small molecule that entered clinical development as a highly selective, non-ATP-competitive inhibitor of the c-MET receptor tyrosine kinase.[1] The c-MET pathway, a critical mediator of cell growth, survival, and metastasis, is frequently dysregulated in human cancers, making it a high-priority target for therapeutic intervention.[2] Tivantinib's unique mechanism, which involved binding to the inactive conformation of the kinase, initially positioned it as a novel and promising agent in the field of targeted oncology.[3]

However, the trajectory of Tivantinib's development is a cautionary tale in pharmaceutical research, defined by a fundamental and consequential misinterpretation of its primary mechanism of action. As the drug progressed, a compelling body of evidence emerged demonstrating that its principal cytotoxic activity did not stem from c-MET inhibition. Instead, Tivantinib functions as a potent antimitotic agent by disrupting microtubule polymerization, a mechanism entirely independent of the c-MET pathway.[5] This critical disconnect between the drug's presumed target and its actual biological function created a foundational flaw in its clinical development strategy.