As one of the last receptor tyrosine kinases identified in the human kinome, AXL of the TAM family remains relatively untapped in the context of drug discovery, partially due to the lack of evidence as an oncogenic driver. Nevertheless, AXL mediates oncogenesis in almost all cancer types, and its expression directly correlates with tumor stage and prognosis. Dysregulation of AXL receptor tyrosine kinase activity has been implicated in the development of drug resistance in a variety of cancers. Activation of AXL underlies the acquired resistance to EGFR kinase inhibitor in non-small cell lung carcinoma. Transactivation of AXL by activation of EGFR may confer the resistance to ErbB family receptor-targeted inhibitors in breast cancer. AXL is upregulated in Gleevec and Tasigna-resistant CML cell lines and patients. Therefore, the impact of targeted inhibition of AXL is at least 3-fold: anti-tumour, anti-metastatic, and anti-chemo-resistance, which provides superior advantages over the existing targeted therapies.
SLC-391 is a specific small molecule AXL inhibitor with desirable potency and pharmaceutical properties. It is a potent with single-digit nanomolar IC50 and good selectivity against other kinases. The pharmacokinetic studies in rodents indicated that this compound has high bioavailability with simple suspension formulation. The in vivo studies of this compound demonstrated efficacy in different animal models including NSCLC, CML and AML models. Moreover, it has exhibited synergy with other approved targeted therapies in different animal models. In addition, this compound promotes anti-tumour immunity through modulation of tumour-associated macrophage polarization. Currently, it is under phase I clinical investigations in multi-cancer centres in Canada. Click here for more information.