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.

中文翻译：

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发现 A-910，一种高效且口服生物利用度的双重 MerTK/Axl 选择性酪氨酸激酶抑制剂


TAM 受体酪氨酸激酶已成为有前途的癌症治疗靶点，因为它们在肿瘤内在生存机制和抑制肿瘤微环境中的抗肿瘤免疫中发挥作用。选择性抑制 MerTK 和 Axl 被认为会阻碍癌细胞存活，逆转促瘤髓系表型，并抑制胞吐作用，从而引发抗肿瘤免疫反应。在这项研究中，我们介绍了 A-910 的发现，这是一种高效且选择性的双重 MerTK/Axl 抑制剂，通过基于结构的药物化学活动实现。该先导化合物表现出良好的口服生物利用度、出色的激酶组选择性，并显著改善体内靶标参与。这些发现支持使用 A-910 作为口服生物可利用的体内工具化合物，用于研究双重 MerTK/Axl 抑制的免疫治疗潜力。