Investigational new drugs, 2023-04, Vol.41 (2), p.254-266
2023
Details
- Autor(en) / Beteiligte
- Titel
- Iruplinalkib (WX‑0593), a novel ALK/ROS1 inhibitor, overcomes crizotinib resistance in preclinical models for non-small cell lung cancer
- Ist Teil von
- Investigational new drugs, 2023-04, Vol.41 (2), p.254-266
- Ort / Verlag
- New York: Springer US
- Erscheinungsjahr
- 2023
- Link zum Volltext
- Quelle
- SpringerNature Journals
- Beschreibungen/Notizen
- Despite remarkable initial responses of anaplastic lymphoma kinase (ALK) inhibitors in ALK -positive non-small cell lung cancer (NSCLC) patients, cancers eventually develop resistance within one to two years. This study aimed to compare the properties of iruplinalkib (WX‑0593) with other ALK inhibitors and report the comprehensive characterization of iruplinalkib against the crizotinib resistance. The inhibitory effect of iruplinalkib on kinase activity was detected. A kinase screen was performed to evaluate the selectivity of iruplinalkib. The effect of iruplinalkib on related signal transduction pathways of ALK and c-ros oncogene 1 (ROS1) kinases was examined. The cellular and in vivo activities of ALK inhibitors were compared in engineered cancer-derived cell lines and in mice xenograft models, respectively. Human hepatocytes derived from three donors were used for evaluating hepatic enzyme inducing activity. HEK293 cell lines expressing transportors were used to invesigated the drug interaction potential mediated by several transporters. The results showed iruplinalkib potently inhibited the tyrosine autophosphorylation of wild-type ALK, ALK L1196M , ALK C1156Y and epidermal growth factor receptor (EGFR) L858R/T790M . The inhibitory effects of iruplinalkib in patient-derived xenograft and cell line-derived xenograft models were observed. Moreover, iruplinalkib showed robust antitumor effects in BALB/c nude mice xenograft models with ALK-/ROS1-positive tumors implanted subcutaneously, and the tumor suppressive effects in crizotinib-resistant model was significantly better than that of brigatinib. Iruplinalkib did not induce CYP1A2, CYP2B6 and CYP3A4 at therapeutic concentration, and was also a strong inhibitor of MATE1 and MATE2K transporters, as well as P-gp and BCRP. In conclusion, iruplinalkib, a highly active and selective ALK/ROS1 inhibitor, exhibited strong antitumor effects in vitro and in crizotinib-resistant models.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0167-6997eISSN: 1573-0646DOI: 10.1007/s10637-023-01350-xTitel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10140010
- Format
- –
- Schlagworte
- Anaplastic Lymphoma Kinase - metabolism, Animal models, Animals, Anticancer properties, Antitumor activity, ATP Binding Cassette Transporter, Subfamily G, Member 2, Carcinoma, Non-Small-Cell Lung - pathology, Cell culture, Cell Line, Tumor, Crizotinib - pharmacology, Crizotinib - therapeutic use, CYP1A2 protein, Cytochrome P450, Drug interaction, Drug interactions, Drug Resistance, Neoplasm, Epidermal growth factor receptors, ErbB Receptors - genetics, Evaluation, Growth factors, HEK293 Cells, Hepatocytes, Humans, Inhibitor drugs, Inhibitors, Kinases, Lung cancer, Lung Neoplasms - pathology, Lymphoma, Medicine, Medicine & Public Health, Mice, Mice, Nude, Mutation, Neoplasm Proteins - metabolism, Non-small cell lung carcinoma, Oncogenes, Oncology, Pharmacology/Toxicology, Protein Kinase Inhibitors - pharmacology, Protein Kinase Inhibitors - therapeutic use, Protein-tyrosine kinase, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Pyridines - therapeutic use, Receptor Protein-Tyrosine Kinases, Signal transduction, Small cell lung carcinoma, Tumor cell lines, Tumors, Tyrosine, Xenografts, Xenotransplantation