Discovery of mobocertinib, a new irreversible tyrosine kinase inhibitor indicated for the treatment of non-small-cell lung cancer harboring EGFR exon 20 insertion mutations

Jun Wang, Daniel Lam, Jeffrey Yang, Longqin Hu

Research output: Contribution to journalReview articlepeer-review

Abstract

Epidermal growth factor receptor (EGFR) is essential for normal cellular functions. Mutations of EGFR’s kinase domain can cause dysregulation leading to non-small cell lung cancer (NSCLC). Exon 20 insertion (ex20ins) mutations in EGFR are one of the leading contributors to oncogenesis and confer insensitivity to most available therapeutics. Mobocertinib is a novel tyrosine kinase inhibitor (TKI) recently approved by the US FDA as a first-in-class small molecule therapeutic for EGFR ex20ins-positive NSCLC. When compared to osimertinib, a TKI indicated for the treatment of EGFR T790M-positive NSCLC, mobocertinib differs only by the presence of an additional C5-carboxylate isopropyl ester group on the middle pyrimidine core. Together with the acrylamide side chain that is responsible for irreversible inhibition, this additional C5-substituent affords mobocertinib high anticancer potency and specificity to EGFR ex20ins-positive lung cancer that is resistant to other EGFR TKIs. This review article provides an overview of the discovery of mobocertinib from osimertinib including their structure-activity relationships, mechanisms of action, preclinical pharmacology, pharmacokinetics, and clinical applications. The discovery and use of mobocertinib and other EGFR TKIs demonstrate the power of structure-based drug design and promising therapeutic outcomes of using precision medicine approaches in the management of molecularly defined tumors. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)1647-1662
Number of pages16
JournalMedicinal Chemistry Research
Volume31
Issue number10
DOIs
StatePublished - Oct 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Keywords

  • Epidermal growth factor receptor (EGFR)
  • Exon 20 insertion mutations (ex20ins)
  • Irreversible tyrosine kinase inhibitor (TKI)
  • Mobocertinib
  • Non-small cell lung cancer (NSCLC)

Fingerprint

Dive into the research topics of 'Discovery of mobocertinib, a new irreversible tyrosine kinase inhibitor indicated for the treatment of non-small-cell lung cancer harboring EGFR exon 20 insertion mutations'. Together they form a unique fingerprint.

Cite this