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

Conspectus 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. Olverembatinib was developed to treat chronic myeloid leukemia patients harboring the gatekeeper Bcr-Abl T315I mutation, which confers resistance to first- and second-generation inhibitors. To mitigate steric clashes and restore lost hydrogen bonding, we introduced an alkyne linker to accommodate conformational shifts, and a 1 H -pyrazolo[3,4- b ]pyridinyl moiety to form new stabilizing hydrogen bonds within the hinge region. For non-small cell lung cancer patients with EGFR T790M -driven resistance, we designed heterocyclic scaffolds bearing electrophilic groups capable of covalently targeting Cys797, enabling high selectivity for EGFR mutants while sparing wild-type EGFR. This approach led to the development of limertinib, a potent and mutant-selective third-generation EGFR inhibitor approved for treating patients with or without EGFR T790M mutations, including those with brain metastases. Building on this success, we are advancing next-generation inhibitors designed to overcome additional resistance mutations such as EGFR L858R/T790M/C797S . In summary, this Account highlights the medicinal chemistry strategies underlying the approvals of olverembatinib and limertinib, illustrating how chemical adaptation can be harnessed to overcome kinase inhibitor resistance. Moving forward, we aim to expand this concept across broader drug modalities and therapeutic targets to address ongoing clinical challenges.