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Abstract
YL143 was identified as a novel wild‐type sparing EGFRT790M inhibitor with good pharmacokinetic properties. It potently suppresses EGFRL858R/T790M with an 50% inhibitory concentration (IC50) value of 2.0 ± 0.3 nmol/L, but is approximately 92‐folds less potent against EGFRWT kinase. YL143 suppresses cellular proliferation and induces G0/G1 phase arrest and apoptosis in H1975 cells with EGFRL858R/T790M mutation at 30 nmol/L. It also exhibits acceptable pharmacokinetics (PK) parameters with an oral bioavailability value of 25.0% after oral administration in rats and exhibits promising antitumor efficacy in a gefitinib‐resistant human H1975 xenografted model after oral administration of 30 mg/kg/day. These data supported that YL143 could be a promising lead compound for overcoming clinical EGFRT790M resistance of patients with non‐small‐cell lung cancer (NSCLC).
Highlights
Lung cancer is a leading cause of cancer-related death worldwide [1, 2]
Primary antibodies against epidermal growth factorYL143 Overcomes T790M Resistance receptor (EGFR) (#4267), phosphor-EGFR (#2234), ERK1/2 (#4695), phosphor-ERK1/2 (#4370), CDK2 (#2546), CDK4 (#2906), cyclin D2 (#3741), cyclin E (#4129), caspase-3 (#9665), caspase-9 (#9502), Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (#2118), and horseradish peroxidase (HRP)- linked secondary antibodies against rabbit or mouse were purchased from Cell Signaling Technology (Boston, MA)
YL143 (Fig. 1A) possesses a novel chemical structure optimized from XTF262 (Fig. S1), which retains its activity and selectivity on EGFRT790M and improves the oral bioavailability (Table 3, S2)
Summary
Lung cancer is a leading cause of cancer-related death worldwide [1, 2]. Non-small-cell lung cancers (NSCLC)that comprise almost 85% of all human lung tumors include squamous cell carcinoma, adenocarcinoma, and large-cell lung cancer [3, 4]. YL143 Overcomes T790M Resistance receptor (EGFR) such as L858R mutation and E746-A750 deletion have been observed in approximately 30% patients with NSCLC and have been identified as key drivers of NSCLC progression [5, 6]. The first-g eneration EGFR kinase inhibitors, for example, gefitinib and erlotinib, produce reliable responses and survival benefits in patients with NSCLC with EGFR activating mutation. 50% of resistant patients harbor a secondary threonine790 to methionine790 mutation in EGFR kinase domain [9]. The second-generation inhibitors such as afatinib were developed with the aim to overcome the EGFRT790M mutation-mediated resistance [10]. Osimertinib had been approved by the FDA to treat the patients who exhibit resistance to gefitinib and erlotinib therapy and harbor EGFRT790M mutation. The clinical investigation of CO1686 was terminated because of the strong IGF1R inhibitory activities of its metabolites causing hyperglycemia in about 40% patients [17,18,19]
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