2-Alkyloxazoles as potent and selective PI4KIIIβ inhibitors demonstrating inhibition of HCV replication

Keaney, Erin P.; Connolly, MJ; Dobler, M.; Karki, Rajeshri G.; Honda, Ayako; Sokup, Samantha; Karur, Subramanian; Britt, Shawn D.; Patnaik, Anup; Raman, Prakash; Hamann, Lawrence G.; Wiedmann, Brigitte; LaMarche, Matthew J.

doi:10.1016/j.bmcl.2014.07.015

Cited by 22 publications

(18 citation statements)

References 21 publications

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“…The same Novartis group has recently published a structure-activity relationship (SAR) study focused on oxazole derivatives that also exert exclusive selectivity toward PI4K IIIβ (Fig. 5(4)) [143]. Waring and colleagues identified PIK93-like scaffold by focused screening of 100,000 compounds from the AstraZeneca library and explored potential enhancement of selectivity of PI4K IIIβ inhibitors resulting in a selective compound with an IC 50 ¼16 nM (Fig.…”

Section: Inhibitors Of Pi4ks and Their Potential In Human Medicinementioning

confidence: 97%

Phosphatidylinositol 4-kinases: Function, structure, and inhibition

Bouřa

Nencka

2015

Experimental Cell Research

126

107

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Section: Inhibitors Of Pi4ks and Their Potential In Human Medicinementioning

confidence: 97%

Phosphatidylinositol 4-kinases: Function, structure, and inhibition

Bouřa

Nencka

2015

Experimental Cell Research

126

107

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“…The acetamide group mediating specificity of PI4KIIIβ inhibitors strongly correlates with previous studies on compounds very similar to compound 1 . Addition of a bulky substituent in a similar position to the acetamide group in compound 1 had a limited role in potency, but greatly enhanced specificity 26,29 . Structural and computational models of a different class of inhibitors bound to PI4KIIIβ suggested an important role of the pocket located near this region in mediating both potency and selectivity 24 .…”

Section: Discussionmentioning

confidence: 99%

Design and Structural Characterization of Potent and Selective Inhibitors of Phosphatidylinositol 4 Kinase IIIβ

et al. 2016

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Type III Phosphatidylinositol 4-kinase (PI4KIIIβ) is an essential enzyme in mediating membrane trafficking, and is implicated in a variety of pathogenic processes. It is a key host factor mediating replication of RNA viruses. The design of potent and specific inhibitors of this enzyme will be essential to define its cellular roles, and may lead to novel anti-viral therapeutics. We previously reported the PI4K inhibitor PIK93, and this compound has defined key functions of PI4KIIIβ. However, this compound showed high cross reactivity with class I and III PI3Ks. Using structure-based drug design we have designed novel potent and selective (>1000 fold over class I and class III PI3Ks) PI4KIIIβ inhibitors. These compounds showed anti-viral activity against Hepatitis C Virus. The co-crystal structure of PI4KIIIβ bound to one of the most potent compounds reveals the molecular basis of specificity. This work will be vital in the design of novel PI4KIIIβ inhibitors, which may play significant roles as anti-viral therapeutics.

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“…The advantages of targeting PITPs for this purpose are that such interventions can be imposed with selectivities superior to those possible by popular strategies that either target individual PtdIns-kinase isoforms or individual PIP species ( 15,16 ). Proof of concept is exemplifi ed by the identifi cation and validation of several classes of small molecule inhibitors (SMIs) that target Sec14, the major PITP of yeast.…”

mentioning

confidence: 99%

Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors

Khan

McGrath

Dorosheva

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org Phosphoinositides (PIPs) are phosphorylated derivatives of phosphatidylinositol (PtdIns), and the metabolism of these lipids constitutes a major membrane-associated signaling system in eukaryotic cells (1)(2)(3)(4)(5). The chemical heterogeneity that distinguishes individual PIP species forms one basis for functionally compartmentalizing signaling platform identities on membrane surfaces ( 6, 7 ). Yet while the chemical heterogeneity of PIP species is simple, it translates to an enormous diversity of biological outcomes that derive from PIP signaling. In that regard, recent studies demonstrate additional layers of functional specifi cation for PIP signaling that are of such resolution that production of an individual PIP species by a specifi c PtdIns kinase yields multiple biological outcomes in the same cell ( 8 ). We now appreciate that PtdIns transfer proteins (PITPs) play critical roles in functional compartmentalization of PIP signaling reactions by channeling PtdIns to PtdIns kinases and, subsequently, to distinct sets of effector proteins ( 9-11 ). The Sec14-like PITPs are best studied in this regard, and the multiplicity of Sec14-like PITPs expressed in even simple unicellular eukaryotes highlights the high degree of functional specifi cation for these proteins ( 12,13 ).Emerging evidence that PITPs instruct the biological outcomes of PtdIns kinase activities recommends these proteins as novel targets for chemical intervention with PIP signaling pathways in cells ( 11,14 ). The advantages of targeting PITPs for this purpose are that such interventions can be imposed with selectivities superior to those possible by popular strategies that either target individual PtdIns-kinase isoforms or individual PIP species ( 15,16 ). Proof of concept is exemplifi ed by the identifi cation and validation of several classes of small molecule inhibitors (SMIs) that target Sec14, the major PITP of yeast. Abbreviations: MM-GBSA, molecular mechanics with generalized born and surface area; NPPM, nitrophenyl(4-(2-methoxyphenyl)piperazin-1-yl)methanone; PDB, Protein Data Bank; PIP, phosphoinositide; PITP, phosphatidylinositol transfer protein; PtdCho, phosphatidylcholine; PtdIns, phosphatidylinositol; SMI, small molecule inhibitor .

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2-Alkyloxazoles as potent and selective PI4KIIIβ inhibitors demonstrating inhibition of HCV replication

Cited by 22 publications

References 21 publications

Phosphatidylinositol 4-kinases: Function, structure, and inhibition

Phosphatidylinositol 4-kinases: Function, structure, and inhibition

Design and Structural Characterization of Potent and Selective Inhibitors of Phosphatidylinositol 4 Kinase IIIβ

Structural elements that govern Sec14-like PITP sensitivities to potent small molecule inhibitors

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