Namekata Kazuhiko, Tsuji Naoki, Guo Xiaoli, Nishijima Euido, Honda Sari, Kitamura Yuta, Yamasaki Atsushi, Kishida Masamichi, Takeyama Jun, Ishikawa Hirokazu, Shinozaki Youichi, Kimura Atsuko, Harada Chikako, Harada Takayuki
Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
R&D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
Cell Death Discov. 2023 May 15;9(1):166. doi: 10.1038/s41420-023-01460-8.
Dedicator of cytokinesis 3 (DOCK3) is an atypical member of the guanine nucleotide exchange factors (GEFs) and plays important roles in neurite outgrowth. DOCK3 forms a complex with Engulfment and cell motility protein 1 (Elmo1) and effectively activates Rac1 and actin dynamics. In this study, we screened 462,169 low-molecular-weight compounds and identified the hit compounds that stimulate the interaction between DOCK3 and Elmo1, and neurite outgrowth in vitro. Some of the derivatives from the hit compound stimulated neuroprotection and axon regeneration in a mouse model of optic nerve injury. Our findings suggest that the low-molecular-weight DOCK3 activators could be a potential therapeutic candidate for treating axonal injury and neurodegenerative diseases including glaucoma.
细胞分裂素3的 dedicator（DOCK3）是鸟嘌呤核苷酸交换因子（GEFs）的非典型成员，在神经突生长中起重要作用。DOCK3与吞噬和细胞运动蛋白1（Elmo1）形成复合物，并有效激活Rac1和肌动蛋白动力学。在本研究中，我们筛选了462,169种低分子量化合物，并鉴定出能刺激DOCK3与Elmo1之间相互作用以及体外神经突生长的活性化合物。活性化合物的一些衍生物在视神经损伤小鼠模型中刺激了神经保护和轴突再生。我们的研究结果表明，低分子量的DOCK3激活剂可能是治疗轴突损伤和包括青光眼在内的神经退行性疾病的潜在治疗候选物。
