Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China.
Eur J Med Chem. 2021 May 5;217:113335. doi: 10.1016/j.ejmech.2021.113335. Epub 2021 Mar 11.
Fusion proteins of the anaplastic lymphoma kinase (ALK) are promising therapeutic targets for cancer and other human diseases, especially for non-small cell lung cancer (NSCLC) and anaplastic large-cell lymphomas (ALCLs). We described herein a structure-based design, synthesis, and evaluation of ALK PROTACs (proteolysis-targeting chimeras) based on Alectinib as the warhead. We firstly screened CRBN ligands as the E3 ligase moiety, then obtained a series of potent ALK degraders based on different CRBN ligands, exemplified by SIAIS091 and SIAIS001 with lenalidomide/thalidomide-based linkers. Both of them induced effective ALK degradation at low nanomolar concentrations in cells, and showed much better growth inhibition effects than Alectinib. SIAIS091 or SIAIS001 also promoted cell cycle arrest in G1/S phase. Finally, SIAIS001 exhibited good oral bioavailability in Pharmacokinetics study.
间变性淋巴瘤激酶（ALK）融合蛋白是癌症和其他人类疾病的有前途的治疗靶点，特别是针对非小细胞肺癌（NSCLC）和间变大细胞淋巴瘤（ALCLs）。本文描述了基于艾乐替尼作为弹头的基于结构的 ALK PROTACs（蛋白水解靶向嵌合体）的设计、合成和评价。我们首先筛选了 CRBN 配体作为 E3 连接酶部分，然后获得了一系列基于不同 CRBN 配体的有效的 ALK 降解剂，以基于来那度胺/沙利度胺的连接子的 SIAIS091 和 SIAIS001 为代表。它们都在细胞中以低纳摩尔浓度诱导有效的 ALK 降解，并表现出比艾乐替尼更好的生长抑制效果。SIAIS091 或 SIAIS001 还促进了细胞周期停滞在 G1/S 期。最后，SIAIS001 在药代动力学研究中表现出良好的口服生物利用度。
