Chemical Adaptation in Drug Discovery: The Medicinal Chemistry Journey of Olverembatinib and Limertinib in Overcoming Kinase Drug Resistance

Abstract

Drug resistance remains one of the biggest challenges in kinase inhibitor therapy, particularly in cancers where prolonged treatment fosters the emergence of resistant mutations. These mutations often alter amino acid residues within the kinase active site, reshaping the local chemical environment and disrupting critical drug-target interactions. The resulting changes – such as steric hindrance, loss of key hydrogen bonds, elimination of reactive residues, or other structural incompatibilities – can drastically reduce drug efficacy. To counter these effects, drug molecules must undergo tailored chemical adaptation – strategic modifications that align their molecular features (e.g., geometric shape, stereochemistry, acidity/basicity, and reactivity) with the mutation-altered changes in steric, electronic, and reactivity landscapes within the mutant kinase binding pocket. In this Account, we describe how the principles of chemical adaptation guided our rational design of small molecule kinase inhibitors to overcome clinically relevant resistance. Over the past 18 years, these efforts have culminated in the discovery and approval of two targeted therapies – olverembatinib and limertinib – as well as the advancement of several clinical-stage candidates.