ap26113 and Lung-Neoplasms

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

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.

Topics: Administration, Oral; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Female; Humans; Lung Neoplasms; Mice; Mice, SCID; Molecular Conformation; Neoplasms, Experimental; Organophosphorus Compounds; Phosphines; Protein Kinase Inhibitors; Pyrimidines; Rats; Receptor Protein-Tyrosine Kinases; Structure-Activity Relationship

The treatment of patients with advanced non-small-cell lung cancer harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small-molecule inhibitor of ALK, ROS1, and MET. However, resistance to crizotinib inevitably develops through a variety of mechanisms, leading to relapse both systemically and in the central nervous system (CNS). This has motivated the development of "second-generation" ALK inhibitors, including alectinib and ceritinib, that overcome some of the mutations leading to resistance. However, most of the reported ALK inhibitors do not show inhibition of the G1202R mutant, which is one of the most common mutations. Herein, we report the development of a structural analogue of alectinib (JH-VIII-157-02) that is potent against the G1202R mutant as well as a variety of other frequently observed mutants. In addition, JH-VIII-157-02 is capable of penetrating the CNS of mice following oral dosing.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lung; Lung Neoplasms; Mice; Molecular Docking Simulation; Neuroblastoma; NIH 3T3 Cells; Piperidines; Point Mutation; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases