Osimertinib | Mutant EGFR kinase inhibitor

Osimertinib (1421373-65-0) is a potent, selective, irreversible inhibitor of mutant EFGR tyrosine kinase.¹ Osimertinib inhibits phosphorylation of EGFR in T790M-mutant cell lines (IC₅₀ <15 nM) but was less potent at inhibition of EGFR phosphorylation in wild-type cells (IC₅₀s in the range of 480 to 1,865 nM). It produces sustained tumor regression in EGFR-mutant tumor xenograft and transgenic rodent models.² Tumor cells develop resistance to osimertinib but combination treatment with an IL-6 antibody reverses resistance to a certain extent.³ In clinical use for treatment of non-small cell lung cancer.⁴

References/Citations:

1. Finlay et al. (2014), Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor; J. Med. Chem., 57 8249
2. Cross et al. (2014), AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer; Cancer Discov., 4 1046
3. Tan et al. (2024), Evaluation of drug resistance for EGFR-TKIs in lung cancer via multicellular lung-on-a-chip; Eur. J. Pharm. Sci., 199 106805
4. Patel et al. (2017); Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance; J. Med. Chem., 142 32