EAI-045

EAI045 is a potent and selective inhibitor of mutant EGF receptors (EGFRs; IC₅₀s = 0.076, 0.049, 0.002, and 1.6 μM for recombinant EGFR^L858R, EGFR^T790M, EGFR^L858R/T790M, and wild-type EGFR, respectively). It inhibits phosphorylation of EGFR in a concentration-dependent manner in H1975 cells. EAI045 (0.01-10 μM) reduces proliferation of Ba/F3 cells expressing EGFR^L858R/T790M and EGFR^{L858R/T790M/I941R}. In vivo, EAI045 induces tumor regression and reduces EGFR signaling in mice bearing EGFR^L858R/T790M, EGFR^{Exon19del/T790M}, and EGFR^{L858R/T790M/C797S} tumors when administered at a dose of 60 mg/kg per day in combination with cetuximab.

EAI045 is a potent and selective EGFR inhibitor (fourth generation). EAI045 targets selected drug-resistant EGFR mutants without affecting the wild-type receptor. EAI045 inhibits L858R/T790M-mutant EGFR with low-nanomolar potency in biochemical assays. Therefore, it is a potential candidate drug for the treatment of related non-small cell lung cancer (NSCLC). It should be noted that EAI-045 is effectively in targeting the EGFR C797S mutation, which is resistance to the third-generation EGFR inhibitors including AZD9291 (osimertinib) and CO-1686 (rociletinib).

Epidermal growth factor receptor (EGFR) is a cell surface receptor often mutated in cancer cells. α-(5-Fluoro-2-hydroxyphenyl)-1,3-dihydro-1-oxo-N-2-thiazolyl-2H-isoindole-2-acetamide is an allosteric EGFR inhibitor that is selective against drug-resistant EGFR mutants.

Wang, S., Y. Song, and D. Liu. "EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance." Cancer Letters385(2017):51.
Jia, Y., et al. "Overcoming EGFR T790M and C797S resistance with mutant-selective allosteric inhibitors:." Nature 534.7605(2016):129.