2. Academic Validation
  3. Discovery of Hepatitis B Virus Surface Antigen Suppressor GS-8873

Discovery of Hepatitis B Virus Surface Antigen Suppressor GS-8873

  • ACS Med Chem Lett. 2024 Mar 22;15(4):546-554. doi: 10.1021/acsmedchemlett.4c00037.
Darryl Kato 1,  Regina Wai-Yan Choy 1,  Eda Canales 1,  Ryan A Dick 2,  April D Lake 1,  Nathan D Shapiro 1,  Elbert Chin 1,  Jiayao Li 1,  Jennifer R Zhang 1,  Qiaoyin Wu 1,  Roland D Saito 1,  Sammy Metobo 3,  Evangelos Aktoudianakis 1,  Scott D Schroeder 1,  Zheng-Yu Yang 1,  Dylan M Glatt 4,  Scott Balsitis 1,  Lindsay Gamelin 1,  Mei Yu 1,  Guofeng Cheng 5,  William E Delaney 4th 6,  John O Link 1
Affiliations

Affiliations

  • 1 Gilead Sciences, Foster City, California 94404, United States.
  • 2 Maze Therapeutics, South San Francisco, California 94080, United States.
  • 3 Circle Pharma, South San Francisco, California 94080, United States.
  • 4 23andMe Therapeutics, South San Francisco, California 94080, United States.
  • 5 AusperBio Therapeutics Inc., San Mateo, California 94401, United States.
  • 6 Assembly Bio, South San Francisco, California 94080, United States.
PMID: 38628802 DOI: 10.1021/acsmedchemlett.4c00037
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145713
    HBV抑制剂
    HBV
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