title: Discovery of a highly potent glucocorticoid for asthma treatment.
abstract: Glucocorticoids are the most effective treatment for asthma. However, their clinical applications are limited by low efficacy in severe asthma and by undesired side effects associated with high dose or prolonged use. The most successful approach to overcome these limitations has been the development of highly potent glucocorticoids that can be delivered to the lungs by inhalation to achieve local efficacy with minimal systemic effects. On the basis of our previous structural studies, we designed and developed a highly potent glucocorticoid, VSGC12, which showed an improved anti-inflammation activity in both cell-based reporter assays and cytokine inhibition experiments, as well as in a gene expression profiling of mouse macrophage RAW264.7 cells. In a mouse asthma model, VSGC12 delivered a higher efficacy than fluticasone furoate, a leading clinical compound, in many categories including histology and the number of differentiated immune cells. VSGC12 also showed a higher potency than fluticasone furoate in repressing most asthma symptoms. Finally, VSGC12 showed a better side effect profile than fluticasone furoate at their respective effective doses, including better insulin response and less bone loss in an animal model. The excellent therapeutic and side effect properties of VSGC12 provide a promising perspective for developing this potent glucocorticoid as a new effective drug for asthma.
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI, USA.
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: He
authors.affiliation: VARI-SIMM Center, Center for Structure and Function of Drug Targets, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Shi
authors.affiliation: VARI-SIMM Center, Center for Structure and Function of Drug Targets, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.affiliation: Department of Medicine, Lung Biology Center, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Ren
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Laboratory of Skeletal Biology, Van Andel Research Institute, Grand Rapids, MI, USA ; College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
authors.forename: Jianshuang
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medicine, Lung Biology Center, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Nanyan
authors.initials: N
authors.lastname: Wu
authors.affiliation: Laboratory of Skeletal Biology, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Weaver
authors.affiliation: Molecular Oncogenesis and Targeted Therapy, Laboratory of Molecular Oncology, Center of Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Cell & Molecular Biology, Grand Valley State University, Grand Rapids, MI, USA.
authors.forename: Sok Kean
authors.initials: SK
authors.lastname: Khoo
authors.affiliation: Laboratory of Skeletal Biology, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Medicine, Lung Biology Center, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Huang
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI, USA.
authors.forename: Karsten
authors.initials: K
authors.lastname: Melcher
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI, USA ; VARI-SIMM Center, Center for Structure and Function of Drug Targets, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
keywords: Glucocorticoids; VSGC12; asthma; glucocorticoid receptor; potency