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
  • 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.

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