Hepatitis B virus (HBV) infection is a serious public health concern with high unmet medical needs. The current therapies, including both nuleos(t)ides and interferon, cannot effectively achieve HBV functional cure with HBsAg loss and subsequently seroconversion. To improve the cure rate, agents with novel mechanisms of action are required. Starting from a phenotypic screening, RG7834, a compound from dihydroquinolizinone (DHQ) chemical series, was discovered as a highly selective HBV inhibitor which can block both viral antigen and viral DNA production. Significant HBsAg reduction was observed in humanized liver mouse model after treatment with RG7834. The mechanism of action of RG7834 is clearly differentiated from the current therapies. Target identification efforts revealed that PAPD5 and PAPD7 are the target proteins for DHQs which had never been reported for HBV therapy. Herein we report the discovery of this first-in-class selective and orally bioavailable small molecule HBV expression inhibitor, as well as the identification of the novel targets.

Discovery of RG7834 and target identification: First-in-class selective and orally bioavailable small molecule HBV expression inhibitor with a novel mechanism of action

2019 Fall National Meeting

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