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  • Small kinase inhibitors have been developed to

    2024-07-10

    Small kinase inhibitors have been developed to block AXL by interacting with the kinase cytoplasmic ATP binding site. Up to date, no AXL selective kinase inhibitors are marketed. As depicted in , some marketed kinase inhibitors such as Bosutinib and Cabozantinib or kinase inhibitors in clinical phases such as Foretinib and BMS777607 inhibit AXL but as a secondary target. To our knowledge, BGB324 also called R428 is the most specific inhibitor of AXL. This molecule is developed by BergenBio and currently in clinical phases 1 and 1/2 for treatment of Acute Myeloid Leukemia and Non Small Cell Lung Cancer respectively. As several other kinase inhibitors with AXL as primary target are in preclinical stages only, developing innovative and specific AXL inhibitors remains a challenging task. In this context, we focused our work in developing new AXL inhibitors based on 7-azaindole scaffold. Indeed, 7-azaindole core has proven to be a scaffold of choice to design bioactive compounds and especially kinase inhibitors as reported by Merour et al. Six examples of 7-azaindole derivatives inhibiting kinases are depicted in . To our knowledge, NPS-1034, a dual Met/Axl inhibitor, is the only 7-azaindole derived inhibitor described to target AXL.
    Axl is a receptor tyrosine kinase (RTK) originally identified from patients with chronic myelogenous leukemia. By use of retroviral screening technology, Axl was shown to regulate endothelial cell migration. Axl is also necessary for in vivo angiogenesis and tumor development in mouse models. Axl stimulation triggers several signaling pathways involved in cellular migration, invasiveness, transformation, and proliferation as well as angiogenesis and resistance to chemotherapeutic agents., High Axl Icotinib is observed in many human tumors where it appears to confer aggressive tumor behavior, leading to tumor dissemination and mortality from metastasis. We therefore sought to further validate and characterize Axl as a therapeutic oncology target by the development of small molecule inhibitors. We describe the development of a series of dual Axl-VEGF-R2 kinase inhibitors culminating in , a diaminotriazole which exhibits antitumor activity comparable to Sunitinib in a mouse xenograft model. Initial goals were to achieve good Axl potency as measured by an in-cell western blot (ICWB) assay. Selectivity over the insulin receptor (INSR) and the closely related RTK Mer were desired., Non specific anti-proliferative or cytotoxic activity (PAD assay) was undesirable. Compounds were also screened against vascular endothelial growth factor receptor 2 (VEGF-R2) due to the known antiangiogenic and antitumor effects of targeting this receptor. We hypothesized that dual Axl/VEGF inhibitors might be very effective oncology therapeutics since multiple biological pathways involved with angiogenesis and tumorogenesis would be targeted. An initial high throughput screen generated an acyl diaminotriazole as a starting point. Lead optimization led to compound . The donor-acceptor-donor triad provided by the diaminotriazole as well as a basic nitrogen optimally spaced 4–5 atoms away from the left-hand side aryl ring were essential to the pharmacophore (). Compound showed a 47 nM cellular EC against Axl, 2.75μM against INSR and 1μM cytotoxicity. Unfortunately had poor aqueous solubility and <1% oral bioavailability in the SD rat making it unsuitable for testing in a xenograft model. A logical next step was to replace the acyl carbonyl with a pyridyl nitrogen (). The dashed line in Fig, 1 indicates a potential intramolecular hydrogen bond between the triazole amino group and the pendant carbonyl group of compound or pyridyl nitrogen of compound . Kinase inhibitors designed to contain pseudo six membered rings formed by intramolecular hydrogen bonding have been reported. Indeed, this hypothesis proved correct as replacing the 4-morpholinophenylcarboxamide of compound with a 2-pyridyl gave compound which showed an Axl EC of 334 nM and a comparable selectivity profile. Since synthesis of a series of substituted 2-pyridyl analogues did not result in improved Axl potency, a series of bicyclic analogues was prepared.