Journal Article Epublish
PubMed: 38628802 DOI: 10.1021/acsmedchemlett.4c00037
Discovery of Hepatitis B Virus Surface Antigen Suppressor GS-8873.
ACS Med Chem Lett 15(4):546-554
Authors: Darryl Kato, Regina Wai-Yan Choy, Eda Canales, Ryan A Dick, April D Lake, Nathan D Shapiro, Elbert Chin, Jiayao Li, Jennifer R Zhang, Qiaoyin Wu, Roland D Saito, Sammy Metobo, Evangelos Aktoudianakis, Scott D Schroeder, Zheng-Yu Yang, Dylan M Glatt, Scott Balsitis, Lindsay Gamelin, Mei Yu, Guofeng Cheng, William E Delaney, John O Link
Affiliations
- Gilead Sciences, Foster City, California 94404, United States.
- Maze Therapeutics, South San Francisco, California 94080, United States.
- Circle Pharma, South San Francisco, California 94080, United States.
- 23andMe Therapeutics, South San Francisco, California 94080, United States.
- AusperBio Therapeutics Inc. San Mateo, California 94401, United States.
- Assembly Bio, South San Francisco, California 94080, United States.
Abstract
Chronic hepatitis B (CHB) virus infection afflicts hundreds of millions of people and causes nearly one million deaths annually. The high levels of circulating viral surface antigen (HBsAg) that characterize CHB may lead to T-cell exhaustion, resulting in an impaired antiviral immune response in the host. Agents that suppress HBsAg could help invigorate immunity toward infected hepatocytes and facilitate a functional cure. A series of dihydropyridoisoquinolizinone (DHQ) inhibitors of human poly(A) polymerases PAPD5/7 were reported to suppress HBsAg in vitro. An example from this class, RG7834, briefly entered the clinic. We set out to identify a potent, orally bioavailable, and safe PAPD5/7 inhibitor as a potential component of a functional cure regimen. Our efforts led to the identification of a dihydropyridophthalazinone (DPP) core with improved pharmacokinetic properties. A conformational restriction strategy and optimization of core substitution led to GS-8873, which was projected to provide deep HBsAg suppression with once-daily dosing.
MeSH
Immunity, Infections, Hepatitis B Virus, Herpesvirus 1, Cercopithecine, Antigens, Surface, T-Lymphocytes, Viruses, Hepatitis B, Chronic