Advancements in ALK Inhibition: The Preclinical Performance of WX-0593

The study introduces a new ALK inhibitor, WX-0593, which targets the ALK protein, a type of tyrosine kinase enzyme linked to various cancers, including non-small cell lung cancer (NSCLC). The EML4-ALK fusion is a key driver in about 5% of NSCLC cases. The research presents the first findings on WX-0593's effectiveness.

The methodology involved measuring WX-0593's impact on various ALK mutations and EGFR mutations using kinase assays, and assessing its ability to hinder the growth of cancer cells in several cell lines. The inhibitor's effect on ALK signaling was studied in NCI-H3122 cells. The antitumor efficacy was tested in four different models of NSCLC, including patient-derived xenograft (PDX) and cell-derived xenograft (CDX) models. The compound's pharmacokinetic and pharmacodynamic properties were evaluated through western blot analysis of treated tumor tissues for various biomarkers.

The results showed that WX-0593 had strong enzymatic activity against ALK and EGFR mutations with low IC50 values. It demonstrated significant anti-proliferative effects in the tested cell lines, and western blot analysis confirmed its ability to inhibit key proteins involved in ALK signaling. In the PDX and CDX models, WX-0593 significantly reduced tumor growth at all tested doses. The tumor samples also indicated that the compound's antitumor effects were due to its inhibition of ALK signaling pathways.

In conclusion, the study identified WX-0593 as a potent second-generation ALK inhibitor with oral bioavailability. It effectively inhibits both wild-type and crizotinib-resistant ALK, exhibiting robust antitumor activity in preclinical models. The findings suggest that WX-0593 is a promising candidate for further clinical development.

The study was presented by Liu Xile and colleagues at the American Association for Cancer Research Annual Meeting in 2018, with the abstract published in the Cancer Research journal.