asp3026 and Carcinoma--Non-Small-Cell-Lung

Epidermal growth factor receptor (EGFR) is a receptor for epithelial growth factor (EGF) cell proliferation and signaling, which is related to the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis, and apoptosis. Thus, it has become an important target for the treatment of non-small cell lung cancer (NSCLC). The first to the third-generation EGFR inhibitors have demonstrated powerful efficacy and brought a prospect to patients. Unfortunately, after 9-15 months of treatment, they all developed resistance without exception. As for the resistance of third-generation inhibitors, no major breakthrough has been made in this field. In this review, we discussed the recent advances in medicinal chemistry of fourth-generation EGFR-TKIs, as well as further discussed the clinical challenges and future prospects of treating patients with EGFR mutations resistant to third-generation EGFR-TKIs.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Chemistry, Pharmaceutical; ErbB Receptors; Humans; Lung Neoplasms; Molecular Structure; Mutation; Protein Kinase Inhibitors

The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein-797 to serine-790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current irreversible EGFR TKIs. In this Miniperspective, we present key mechanisms of resistance in response to third-generation EGFR TKIs, and emerging reports on novel EGFR TKIs to combat the resistance. Specifically, we analyze the allosteric and ATP-competitive inhibitors in terms of drug discovery, binding mechanism, and their potency and selectivity against EGFR harboring C797S mutations. Lastly, we provide some perspectives on new challenges and future directions in this field.

Topics: Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitors

Anaplastic lymphoma kinase (ALK) is a validated therapeutic target for treating echinoderm microtubule-associated protein-like 4 (EML4)-ALK positive non-small cell lung cancer (NSCLC). We synthesized a series of 1,3,5-triazine derivatives and identified ASP3026 (14a) as a potent and selective ALK inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, once-daily oral administration of 14a demonstrated dose-dependent antitumor activity. Here, syntheses and structure-activity relationship (SAR) studies of 1,3,5-triazine derivatives are described.

Topics: Administration, Oral; Anaplastic Lymphoma Kinase; Animals; Binding Sites; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Administration Schedule; Drug Evaluation, Preclinical; Humans; Inhibitory Concentration 50; Lung Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Docking Simulation; Protein Kinase Inhibitors; Protein Structure, Tertiary; Receptor Protein-Tyrosine Kinases; Structure-Activity Relationship; Sulfones; Transplantation, Heterologous; Triazines

Activation of anaplastic lymphoma receptor tyrosine kinase (ALK) is involved in the pathogenesis of several carcinomas, including non-small cell lung cancer (NSCLC). Echinoderm microtubule-associated protein like 4 (EML4)-ALK, which is derived from the rearrangement of ALK and EML4 genes, has been validated as a therapeutic target in a subset of patients with NSCLC. Here, we investigated the effects of ASP3026, a novel small-molecule ALK inhibitor, against ALK-driven NSCLC. ASP3026 inhibited ALK activity in an ATP-competitive manner and had an inhibitory spectrum that differed from that of crizotinib, a dual ALK/MET inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, orally administered ASP3026 was well absorbed in tumor tissues, reaching concentrations >10-fold higher than those in plasma, and induced tumor regression with a wide therapeutic margin between efficacious and toxic doses. In the same mouse model, ASP3026 enhanced the antitumor activities of paclitaxel and pemetrexed without affecting body weight. ASP3026 also showed potent antitumor activities, including tumor shrinkage to a nondetectable level, in hEML4-ALK transgenic mice and prolonged survival in mice with intrapleural NCI-H2228 xenografts. In an intrahepatic xenograft model using NCI-H2228 cells, ASP3026 induced continuous tumor regression, whereas mice treated with crizotinib showed tumor relapse after an initial response. Finally, ASP3026 exhibited potent antitumor activity against cells expressing EML4-ALK with a mutation in the gatekeeper position (L1196M) that confers crizotinib resistance. Taken together, these findings indicate that ASP3026 has potential efficacy for NSCLC and is expected to improve the therapeutic outcomes of patients with cancer with ALK abnormality.

Topics: 3T3 Cells; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Cell Survival; Drug Synergism; Glutamates; Guanine; Humans; Immunoblotting; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Molecular Structure; Paclitaxel; Pemetrexed; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Sulfones; Survival Analysis; Triazines; Tumor Burden; Xenograft Model Antitumor Assays