East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, P.R. China.
Joint Center for Translational Medicine, Southern Medical University Affiliated Fengxian Hospital, Shanghai, 201499, P.R. China.
Clin Transl Med. 2021 Feb;11(2):e289. doi: 10.1002/ctm2.289.
As a pivotal vesicular trafficking protein, Myoferlin (MYOF) has become an attractive target for cancer therapy. However, the roles of MYOF in colorectal cancer invasion remain enigmatic, and MYOF-targeted therapy in this malignancy has not been explored. In the present study, we provided the first functional evidence that MYOF promoted the cell invasion of colorectal cancer. Furthermore, we identified a novel small molecule inhibitor of MYOF (named YQ456) that showed high binding affinity to MYOF (K = 37 nM) and excellent anti-invasion capability (IC = 110 nM). YQ456 was reported for the first time to interfere with the interactions between MYOF and Ras-associated binding (Rab) proteins at low nanomolar levels. This interference disrupted several vesicle trafficking processes, including lysosomal degradation, exosome secretion, and mitochondrial dynamics. Further, YQ456 exhibited excellent inhibitory effects on the growth and invasiveness of colorectal cancer. As the first attempt, the anticancer efficacy of YQ456 in the patient-derived xenograft (PDX) mouse model indicated that targeting MYOF may serve as a novel and practical therapeutic approach for colorectal cancer.
作为一种重要的囊泡运输蛋白，肌球蛋白重链（Myoferlin，MYOF）已成为癌症治疗的一个有吸引力的靶点。然而，MYOF 在结直肠癌侵袭中的作用仍然是一个谜，针对这种恶性肿瘤的 MYOF 靶向治疗尚未得到探索。在本研究中，我们提供了第一个功能证据，表明 MYOF 促进了结直肠癌细胞的侵袭。此外，我们鉴定了一种 MYOF 的新型小分子抑制剂（命名为 YQ456），它对 MYOF 具有高结合亲和力（K = 37 nM）和优异的抗侵袭能力（IC = 110 nM）。YQ456 首次被报道在低纳摩尔水平上干扰 MYOF 与 Ras 相关结合（Rab）蛋白之间的相互作用。这种干扰破坏了几种囊泡运输过程，包括溶酶体降解、外泌体分泌和线粒体动力学。此外，YQ456 对结直肠癌细胞的生长和侵袭具有优异的抑制作用。作为首次尝试，YQ456 在患者来源的异种移植（PDX）小鼠模型中的抗癌功效表明，靶向 MYOF 可能成为结直肠癌的一种新的实用治疗方法。
