Osimertinib, Methanesulfonate Salt

Soluble in DMSO. This research compound is the methanesulfonate salt form of osimertinib. Osimertinib, also known as AZD9291, is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). EGFR TKIs have been used to treat patients with non-small-cell lung cancer (NSCLC) harboring sensitizing mutations. However, resistance develops in many patients, mainly because of the T790M mutation leading to disease progression. Furthermore, EGFR wild type receptor inhibition inherent with these EGFR TKIs can lead to dose-limiting toxicities. Osimertinib is an early, mutant selective, irreversible inhibitor of both EGFR mutant (EGFRm+) sensitizing and T790M resistance mutations with selectivity over the wild type form of the receptor. Finlay M.R., et al. '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: 8249-8267 (2014). This research compound is the free base form of osimertinib. We also offer the methanesulfonate salt and dimethansulfonate salt forms, please see Osimertinib, Methanesulfonate Salt, Cat. No. O-7233 and Osimertinib, Dimethanesulfonate Salt Cat. No. O-7266. These two other forms of osimertinib will be available shortly. Osimertinib inhibited EGFR phosphorylation in EGFR-bearing cells harboring sensitizing EGFR mutants with mean IC50 values ranging from 13 to 54 nM. It also potently inhibited phosphorylation of EGFR in T790M+ mutant cell lines, with mean IC50 potency less than 15 nM. However, it was less potent at inhibiting phosphorylation of EGFR in wild-type cell lines with mean IC50 range of 480 to 1,865 nM. Osimertinib demonstrated profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The clinical activities of osimertinib were initially confirmed with the treatment of two patients with advanced EGFRm(+) T790M(+) non-small-cell lung cancer (NSCLC). Cross D.A., et al. 'AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.' Cancer Discov. 4: 1046-1061 (2014). A phase I clinical study showed that osimertinib had robust efficacy in EGFR mutant NSCLC patients with acquired resistance to EGFR-TKIs. Overall response rate (ORR) was 51%. The ORR was 64% in 89 EGFR T790M positive patients and 23% in 43 EGFR T790M negative patients. The overall disease control rate was 96% in T790M positive patients. It was well tolerated. Jiang T. and Zhou C. 'Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients with EGFR inhibitor-resistant non-small cell lung cancer.' Transl. Lung Cancer Res. 6: 370-372 (2014).