Reference Detail

Ref Type

Journal Article

PMID

(37036582)

Authors

Yang Y, Zheng Q, Wang X, Zhao S, Huang W, Jia L, Ma C, Liu S, Zhang Y, Xin Q, Sun Y, Zheng S

Title

Iruplinalkib (WX‑0593), a novel ALK/ROS1 inhibitor, overcomes crizotinib resistance in preclinical models for non-small cell lung cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs	41	2	2023 Apr	254-266	Invest New Drugs

URL

Abstract Text

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, ALKL1196M, ALKC1156Y 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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK	lung non-small cell carcinoma	sensitive	Brigatinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Alunbrig (brigatinib) inhibited tumor growth in a non-small cell lung cancer cell line xenograft model harboring EML4-ALK (PMID: 37036582).	37036582
EML4 - ALK	lung non-small cell carcinoma	sensitive	Crizotinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Xalkori (crizotinib) inhibited tumor growth in a non-small cell lung cancer cell line xenograft model harboring EML4-ALK (PMID: 37036582).	37036582
EML4 - ALK	lung non-small cell carcinoma	sensitive	Iruplinalkib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Iruplinalkib (WX-0593) inhibited tumor growth in a non-small cell lung cancer cell line xenograft model harboring EML4-ALK (PMID: 37036582).	37036582