Ng Pearly Shuyi, Foo Klement, Sim Sandra, Wang Gang, Huang Chuhui, Tan Li Hong, Poulsen Anders, Liu Boping, Tee Doris Hui Ying, Ahmad Nur Huda Binte, Wang Sifang, Ke Zhiyuan, Lee May Ann, Kwek Zekui P, Joy Joma, Anantharajan Jothi, Baburajendran Nithya, Pendharkar Vishal, Manoharan Vithya, Vuddagiri Susmitha, Sangthongpitag Kanda, Hill Jeffrey, Keller Thomas H, Hung Alvin W
Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, 138670, Singapore.
Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, 138670, Singapore.
Bioorg Med Chem. 2021 Nov 1;49:116437. doi: 10.1016/j.bmc.2021.116437. Epub 2021 Sep 25.
AXL is a member of the TAM (TYRO3, AXL, MER) subfamily of receptor tyrosine kinases. It is upregulated in a variety of cancers and its overexpression is associated with poor disease prognosis and acquired drug resistance. Utilizing a fragment-based lead discovery approach, a new indazole-based AXL inhibitor was obtained. The indazole fragment hit 11, identified through a high concentration biochemical screen, was expeditiously improved to fragment 24 by screening our in-house expanded library of fragments (ELF) collection. Subsequent fragment optimization guided by docking studies provided potent inhibitor 54 with moderate exposure levels in mice. X-ray crystal structure of analog 50 complexed with the I650M mutated kinase domain of Mer revealed the key binding interactions for the scaffold. The good potency coupled with reasonable kinase selectivity, moderate in vivo exposure levels, and availability of structural information for the series makes it a suitable starting point for further optimization efforts.
AXL是受体酪氨酸激酶TAM（TYRO3、AXL、MER）亚家族的成员。它在多种癌症中上调，其过表达与疾病预后不良和获得性耐药相关。利用基于片段的先导化合物发现方法，获得了一种新的基于吲唑的AXL抑制剂。通过高浓度生化筛选鉴定出的吲唑片段命中物11，通过筛选我们内部扩展的片段文库（ELF）集合迅速优化为片段24。随后在对接研究指导下的片段优化提供了在小鼠体内具有中等暴露水平的强效抑制剂54。与Mer的I650M突变激酶结构域复合的类似物50的X射线晶体结构揭示了支架的关键结合相互作用。该系列化合物具有良好的活性、合理的激酶选择性、中等的体内暴露水平以及结构信息的可用性，使其成为进一步优化的合适起点。
