Advanced Science (Jul 2020)
Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion
- Zhongya Sun,
- Hao Zhang,
- Yuanyuan Zhang,
- Liping Liao,
- Wen Zhou,
- Fengcai Zhang,
- Fulin Lian,
- Jing Huang,
- Pan Xu,
- Rukang Zhang,
- Wenchao Lu,
- Mingrui Zhu,
- Hongru Tao,
- Feng Yang,
- Hong Ding,
- Shijie Chen,
- Liyan Yue,
- Bing Zhou,
- Naixia Zhang,
- Minjia Tan,
- Hualiang Jiang,
- Kaixian Chen,
- Bo Liu,
- Chuanpeng Liu,
- Yongjun Dang,
- Cheng Luo
Affiliations
- Zhongya Sun
- School of Life Science and Technology Harbin Institute of Technology Harbin 150001 China
- Hao Zhang
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Yuanyuan Zhang
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Liping Liao
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Wen Zhou
- The Second Clinical Medical College, and Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome Guangzhou University of Chinese Medicine Guangzhou 510006 China
- Fengcai Zhang
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Fulin Lian
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Jing Huang
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Pan Xu
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Rukang Zhang
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Wenchao Lu
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Mingrui Zhu
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Hongru Tao
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Feng Yang
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Hong Ding
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Shijie Chen
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Liyan Yue
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Bing Zhou
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Naixia Zhang
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Minjia Tan
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Hualiang Jiang
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Kaixian Chen
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- Bo Liu
- The Second Clinical Medical College, and Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome Guangzhou University of Chinese Medicine Guangzhou 510006 China
- Chuanpeng Liu
- School of Life Science and Technology Harbin Institute of Technology Harbin 150001 China
- Yongjun Dang
- Key Laboratory of Metabolism and Molecular Medicine the Ministry of Education Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Department of Pulmonary and Critical Care Medicine Huashan Hospital Fudan University Shanghai 200032 China
- Cheng Luo
- Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
- DOI
- https://doi.org/10.1002/advs.202000098
- Journal volume & issue
-
Vol. 7,
no. 14
pp. n/a – n/a
Abstract
Abstract The Rho family GTPases are crucial drivers of tumor growth and metastasis. However, it is difficult to develop GTPases inhibitors due to a lack of well‐characterized binding pockets for compounds. Here, through molecular dynamics simulation of the RhoA protein, a groove around cysteine 107 (Cys107) that is relatively well‐conserved within the Rho family is discovered. Using a combined strategy, the novel inhibitor DC‐Rhoin is discovered, which disrupts interaction of Rho proteins with guanine nucleotide exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs). Crystallographic studies reveal that the covalent binding of DC‐Rhoin to the Cys107 residue stabilizes and captures a novel allosteric pocket. Moreover, the derivative compound DC‐Rhoin04 inhibits the migration and invasion of cancer cells, through targeting this allosteric pocket of RhoA. The study reveals a novel allosteric regulatory site within the Rho family, which can be exploited for anti‐metastasis drug development, and also provides a novel strategy for inhibitor discovery toward “undruggable” protein targets.
Keywords