Abstract 1961: Discovery of a highly potent and brain penetrant fourth generation EGFR tyrosine kinase inhibitor

Abstract Third generation EGFR tyrosine kinase inhibitors (TKIs) such as Osimertinib have emerged as first-line standard of care therapy to treat non-small cell lung cancer (NSCLC) patients with activating EGFR mutations (del19, L858R or T790M). However, within 12 to 18 months following treatment, 15-20% of the patients develop C797S mutation, which drives resistance to these drugs; with the progression of disease brain metastasis is observed in 40-70% of the EGFRm+ NSCLC patients. Here, we report a highly potent and brain penetrant fourth generation EGFR-TKI ACE-34237307, designed to overcome C797S mutation (del19/C797S and L858R/C797S), and common single point mutations (del19 and L858R). ACE-34237307 is also designed to potently inhibit the more prevalent non-canonical EGFR mutations such as G719S and L861Q. ACE-34237307 showed robust anti-proliferative activity against EGFR double mutations in Ba/F3 (EGFR-del19/C797S and EGFR-L858R/C797S) cell lines with IC50 values of 0. 1 and 0. 23 nM, respectively. In phospho-EGFR assay, ACE-34237307 demonstrates over 79-fold selectivity against A431 (EGFR-WT) cell line when compared to PC-9 (EGFR-del 19) cell line. ACE-34237307 is highly brain penetrant with B/P ratio of 2. 3 in rat and 1. 2 in mouse. It has an excellent pharmacokinetic profile in rat, mouse and dog with good bioavailability, a flat PK curve and reduced Cmax, which will translate to a better safety profile. The in vivo anti-tumor efficacy was evaluated in Osimertinib resistant double mutant Ba/F3-EGFR-del19/C797S and L858R/C797S as well as del19 and L858R single mutant xenograft models. It has been shown that ACE-34237307 at doses of ≥ 0. 6 mg/kg induces complete tumor regression or eradication in all tumor models tested. In brain tumor models with Ba/F3 (EGFR-del19/C797S) and PC-9 (EGFR-del19), ACE-34237307 showed complete inhibition or eradication of brain tumors and drastically extended animal survival at ≥ 0. 6 mg/kg. In summary, ACE-34237307 is a potent fourth generation EGFR-TKI with high WT selectivity, excellent brain penetration, highly favorable DMPK profile, outstanding in vivo efficacy in subcutaneous and brain tumor models and low projected human dose amenable to QD dosing. Citation Format: sanjeev kumar, junmei wang, wenqian li, weitao pan, zhiming wen, Kuo-Long yu, Genshi Zhao, tinggui yin. Discovery of a highly potent and brain penetrant fourth generation EGFR tyrosine kinase inhibitor abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1961.