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Anti-HCV activity and toxicity of PI4KIIIβ inhibitors

Lamarche, Matthew and Borawski, Jason and Bose, Avirup and Capacci-Daniel, Christina and Colvin, Richard and Dennehy, Michelle and Ding, Jian and Drumm Iii, Joseph and Gaither, Larry and Gao, Jiaping and Jiang, Xiaoqun and Lin, Kai and Mckeever, Una and Puyang, Xiaoling and Raman, Prakash and Thohan, Sanjeev and Tommasi, Ruben and Wagner, Kathrin and Xiong, Xiaowei and Zabawa, Thomas and Zhu, Shejin and Wiedmann, Brigitte (2012) Anti-HCV activity and toxicity of PI4KIIIβ inhibitors. Antimicrobial Agents and Chemotherapy. ISSN 0066-4804

Abstract

Type III phosphatidylinositol-4-kinase beta (PI4KIIIβ) was previously implicated in hepatitis C virus (HCV) replication by siRNA depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIIIβ inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virus in vitro. Replicon cells required more than five weeks to reach low levels of three to five-fold resistance indicating a high resistance barrier to these cellular targets. Extensive in vitro profiling of the compounds revealed a role of PI4KIIIβ in lymphocyte proliferation. Previously proposed functions of PI4KIIIβ in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIIIβ inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected anti-proliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C.

Item Type: Article
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Additional Information: This manuscript has been re-submitted since necessary approval changes were not possible in OAK. The manuscript has not been changed at all.
Keywords: Hepatitis C virus, small molecule inhibitor, proliferation, toxicity
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/7288

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