Discovery of A‑910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor

TAM receptor tyrosine kinases have emerged as promising
therapeutic
targets for cancer treatment due to their roles in both tumor intrinsic
survival mechanisms and suppression of antitumor immunity within the
tumor microenvironment. Inhibiting MerTK and Axl selectively is believed
to hinder cancer cell survival, reverse the protumor myeloid phenotype,
and suppress efferocytosis, thereby eliciting an antitumor immune
response. In this study, we present the discovery of A-910, a highly potent and selective dual MerTK/Axl inhibitor, achieved
through a structure-based medicinal chemistry campaign. The lead compound
exhibits favorable oral bioavailability, exceptional kinome selectivity,
and significantly improved in vivo target engagement. These findings
support the use of A-910 as an orally bioavailable in
vivo tool compound for investigating the immunotherapy potential of
dual MerTK/Axl inhibition.

TAM受体酪氨酸激酶（TAM receptor tyrosine kinases）因同时参与肿瘤内在存活机制与肿瘤微环境内的抗肿瘤免疫抑制，已成为颇具潜力的癌症治疗靶点。选择性抑制MerTK与Axl被认为可阻碍癌细胞存活、逆转促肿瘤髓系表型，并抑制胞葬作用（efferocytosis），进而诱发抗肿瘤免疫应答。本研究通过基于结构的药物化学研发项目，发现了强效高选择性的双靶点MerTK/Axl抑制剂A-910。该先导化合物展现出良好的口服生物利用度、优异的激酶组选择性，且体内靶点结合活性显著提升。上述研究结果支持将A-910作为可口服的体内工具化合物，用于探究双靶点MerTK/Axl抑制的免疫治疗潜力。