title: Anti-hepatitis C virus activity and toxicity of type III phosphatidylinositol-4-kinase beta inhibitors.
abstract: Type III phosphatidylinositol-4-kinase beta (PI4KIIIβ) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (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 5 weeks to reach low levels of 3- to 5-fold resistance, suggesting 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 antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C.
authors: Novartis Institutes for Biomedical Research Inc., Cambridge, Massachusetts, USA.
authors: M J
authors: MJ
authors: Lamarche
authors: J
authors: J
authors: Borawski
authors: A
authors: A
authors: Bose
authors: C
authors: C
authors: Capacci-Daniel
authors: R
authors: R
authors: Colvin
authors: M
authors: M
authors: Dennehy
authors: J
authors: J
authors: Ding
authors: M
authors: M
authors: Dobler
authors: J
authors: J
authors: Drumm
authors: L A
authors: LA
authors: Gaither
authors: J
authors: J
authors: Gao
authors: X
authors: X
authors: Jiang
authors: K
authors: K
authors: Lin
authors: U
authors: U
authors: McKeever
authors: X
authors: X
authors: Puyang
authors: P
authors: P
authors: Raman
authors: S
authors: S
authors: Thohan
authors: R
authors: R
authors: Tommasi
authors: K
authors: K
authors: Wagner
authors: X
authors: X
authors: Xiong
authors: T
authors: T
authors: Zabawa
authors: S
authors: S
authors: Zhu
authors: B
authors: B
authors: Wiedmann
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000998:Antiviral Agents; D019870:1-Phosphatidylinositol 4-Kinase