Design and Synthesis of TASIN Analogues Specifically Targeting Colorectal Cancer Cell Lines with Mutant Adenomatous Polyposis Coli (APC)

Despite advances in targeted anticancer therapies, there are still no small-molecule-based therapies available that specifically target colorectal cancer (CRC) development and progression, the second leading cause of cancer deaths. We previously disclosed the discovery of truncating adenomatous polyposis coli (APC)-selective inhibitor 1 (TASIN-1), a small molecule that specifically targets colorectal cancer cells lines with truncating mutations in the adenomatous polyposis coli (APC) tumor suppressor gene through inhibition of cholesterol biosynthesis. Here, we report a medicinal chemistry evaluation of a collection of TASIN analogues and activity against colon cancer cell lines and an isogenic cell line pair reporting on the status of APC-dependent selectivity. A number of potent and selective analogues were identified, including compounds with good metabolic stability and pharmacokinetic properties. The compounds reported herein represent a first-in-class genotype-selective series that specifically target apc mutations present in the majority of CRC patients and serve as a translational platform toward a targeted therapy for colon cancer.

尽管靶向抗癌疗法已取得诸多进展，但目前仍无基于小分子的疗法可专门针对作为癌症相关死亡第二大诱因的结直肠癌（colorectal cancer, CRC）的发生与发展。我们此前曾报道截短型腺瘤性结肠息肉病（adenomatous polyposis coli, APC）选择性抑制剂1（TASIN-1）的发现：该小分子化合物可通过抑制胆固醇生物合成，特异性靶向腺瘤性结肠息肉病（APC）抑癌基因存在截短突变的结直肠癌细胞系。本文报道了一系列TASIN类似物的药物化学评价结果，及其针对结肠癌细胞系与一组可反映APC依赖性选择性状态的同基因细胞系对的活性。研究鉴定出多个兼具强效性与选择性的类似物，其中部分化合物具备良好的代谢稳定性与药代动力学特性。本文报道的化合物属于同类首创的基因型选择性系列，可特异性靶向存在于大多数结直肠癌患者体内的APC突变，可作为结直肠癌靶向治疗的转化研究平台。