Abstract
AC0010 is a pyrrolopyrimidine-based irreversible EGFR inhibitor, structurally distinct from previously reported pyrimidine-based irreversible EGFR inhibitors, such as osimertinib and rociletinib. AC0010 selectively inhibits EGFR-active and T790M mutations with up to 298-fold increase in potency compared with wild-type EGFR. In a xenograft model, oral administration of AC0010 at a daily dose of 500 mg/kg resulted in complete remission of tumors with EGFR-active and T790M mutations for over 143 days with no weight loss. Three major metabolites of AC0010 were tested and showed no wild-type EGFR inhibition or off-target effects, such as inhibition of IGF-1R. AC0010 is safe in non-small cell lung cancer (NSCLC) patients at a dose range between 50 and 550 mg once per day, and no hyperglycemia or other severe adverse effects were detected, such as grade 3 QT prolongation. The objective responses were observed in NSCLC patients with EGFR T790M mutation. Mol Cancer Ther; 15(11); 2586-97. ©2016 AACR.
Highlights
Non–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and is often insidious, and around 80% of patients have more advanced disease, including 25% of patients with regional metastasis and 55% of patients with distant spread of disease [1, 2]
A more comprehensive molecular understanding of the pathology of NSCLC has led to the development of small molecules that target genetic mutations known to play critical roles in the progression to the metastatic disease in NSCLC patients, such as mutations in EGFR and ALK [3,4,5]
The acrylamide groups on both WZ4002 and AC0010 are at a position that molecular modeling predicts to react with Cys797 (Fig. 1B, middle and right) and form H-bonds to Met793 backbone amide and carbonyl
Summary
Non–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and is often insidious, and around 80% of patients have more advanced disease, including 25% of patients with regional metastasis and 55% of patients with distant spread of disease [1, 2]. A more comprehensive molecular understanding of the pathology of NSCLC has led to the development of small molecules that target genetic mutations known to play critical roles in the progression to the metastatic disease in NSCLC patients, such as mutations in EGFR and ALK [3,4,5]. EGFR is expressed on the cell surface of a substantial percentage of NSCLCs, and 15% to 40% of total NSCLC patients harbor mutations in EGFR. Studies with the EGFR tyrosine kinase inhibitors (TKI), gefitinib and erlotinib, demonstrated biological and clinical activity in a subset of lung cancers harboring EGFR-active mutations, such as small deletions (delE747–750) and point mutation at codon. WZ4002, and two clinical compounds, osimertinib and rociletinib, reported as third-generation EGFR TKIs, demonstrated the inhibition of EGFR T790M-resistant mutation in animal models and in patients [17,18,19]
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