Development of highly potent glucocorticoids for steroid-resistant severe asthma

Yuanzheng He; Jingjing Shi; Quang Tam Nguyen; Erli You; Hongbo Liu; Xin Ren; Zhongshan Wu; Jianshuang Li; Wenli Qiu; Sok Kean Khoo; Tao Yang; Wei Yi; Feng Sun; Zhijian Xi; Xiaozhu Huang; Karsten Melcher; Booki Min; H Eric Xu

doi:10.1073/pnas.1816734116

Development of highly potent glucocorticoids for steroid-resistant severe asthma

Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):6932-6937. doi: 10.1073/pnas.1816734116. Epub 2019 Mar 20.

Authors

Yuanzheng He^{1

2}, Jingjing Shi³, Quang Tam Nguyen⁴, Erli You³, Hongbo Liu⁵, Xin Ren⁶, Zhongshan Wu⁷, Jianshuang Li⁸, Wenli Qiu⁶, Sok Kean Khoo⁹, Tao Yang⁸, Wei Yi^{10

11

12}, Feng Sun⁷, Zhijian Xi⁷, Xiaozhu Huang⁶, Karsten Melcher², Booki Min¹³, H Eric Xu^{14

3}

Affiliations

¹ Laboratory of Receptor Structure and Signaling, HIT Center for Life Science, Harbin Institute of Technology, Harbin 150001, China; ajian.he@hit.edu.cn yiwei@gzhmu.edu.cn minb@ccf.org eric.xu@vai.org.
² Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503.
³ Van Andel Research Institute-Shanghai Institute of Materia Medica, Center for Structure and Function of Drug Targets, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.
⁵ Center of Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503.
⁶ Department of Medicine, Lung Biology Center, University of California, San Francisco, CA 94158.
⁷ Department of Research and Development, Palo Alto Pharmaceuticals, Shanghai 201203, China.
⁸ Laboratory of Skeletal Biology, Van Andel Research Institute, Grand Rapids, MI 49503.
⁹ Department of Cell and Molecular Biology, Grand Valley State University, Grand Rapids, MI 49401.
¹⁰ Van Andel Research Institute-Shanghai Institute of Materia Medica, Center for Structure and Function of Drug Targets, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; ajian.he@hit.edu.cn yiwei@gzhmu.edu.cn minb@ccf.org eric.xu@vai.org.
¹¹ Key Laboratory of Molecular Target and Clinical Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.
¹² State Key Lab of Respiratory Disease, Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.
¹³ Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; ajian.he@hit.edu.cn yiwei@gzhmu.edu.cn minb@ccf.org eric.xu@vai.org.
¹⁴ Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503; ajian.he@hit.edu.cn yiwei@gzhmu.edu.cn minb@ccf.org eric.xu@vai.org.

Abstract

Clinical application of inhaled glucocorticoids (GCs) has been hampered in the case of steroid-resistant severe asthma. To overcome this limitation, we have developed a series of highly potent GCs, including VSGC12, VSG158, and VSG159 based on the structural insight into the glucocorticoid receptor (GR). Particularly, VSG158 exhibits a maximal repression of lung inflammation and is 10 times more potent than the currently most potent clinical GC, Fluticasone Furoate (FF), in a murine model of asthma. More importantly, VSG158 displays a unique property to reduce neutrophilic inflammation in a steroid-resistant airway inflammation model, which is refractory to clinically available GCs, including dexamethasone and FF. VSG158 and VSG159 are able to deliver effective treatments with reduced off-target and side effects. In addition, these GCs also display pharmacokinetic properties that are suitable for the inhalation delivery method for asthma treatment. Taken together, the excellent therapeutic and side-effect profile of these highly potent GCs holds promise for treating steroid-resistant severe asthma.

Keywords: VSG158; VSG159; glucocorticoid; high potency; steroid-resistant asthma.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Asthmatic Agents* / chemistry
Anti-Asthmatic Agents* / pharmacology
Asthma / drug therapy*
Asthma / pathology
Disease Models, Animal
Drug Development*
Female
Glucocorticoids* / chemistry
Glucocorticoids* / pharmacology
Male
Mice
Receptors, Glucocorticoid / agonists
Severity of Illness Index

Substances

Anti-Asthmatic Agents
Glucocorticoids
Receptors, Glucocorticoid

Abstract

Publication types

MeSH terms

Substances

Grants and funding