Targeting Axl Overexpression: The Efficacy of Novel Dual Inhibitor CT413 in Tumor Growth Suppression

Receptor tyrosine kinases are crucial in cell signaling and have emerged as significant targets for cancer treatment. The TAM family, which includes Axl, Mer, and Tyro-3, is particularly noteworthy, with Axl being a prominent candidate for inhibiting cancer's spread and progression. Despite the existence of FDA-approved drugs and those in clinical trials that target Axl and Mer, there is a gap in the market for a specific inhibitor designed for these receptors. The development of dual Axl and Mer inhibitors is seen as a significant step forward in combating malignancies.

CT413, a new oral Axl/Mer inhibitor, is in the preclinical stage of development. It has shown strong inhibitory effects on Axl and Mer with IC50 values of 4 nM and less than 1 nM, respectively. It also inhibits Met and Ron kinases with respective IC50 values of 3 nM and 9 nM. CT413 has displayed high selectivity in both biochemical and cell-based assays, blocking autophosphorylation of Axl, Met, and Ron with varying IC50 values. In animal models, CT413 has significantly reduced tumor growth, with notable tumor growth inhibition (TGI) percentages in different tumor types when administered orally at a dosage of 30 mg/kg once daily. It has shown no significant impact on various CYP450 subtypes and has a low IC50 at the hERG sodium ion channel, suggesting minimal cardiac risk. CT413 has also demonstrated good metabolic stability and favorable pharmacokinetics across different animal species, with high oral bioavailability ranging from 68% to 133%. Non-GLP 28-day toxicity studies have shown that CT413 has a broad therapeutic window. These positive findings have led to the advancement of CT413 as a potential clinical candidate for cancer treatment.

The study, conducted by Ning Xi and colleagues, highlights CT413 as a potent inhibitor of Axl overexpressing tumors and was presented at the 106th Annual Meeting of the American Association for Cancer Research.