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Concise SAR Exploration Based on the "Head-to-Tail" Approach: Discovery of PI4KIII? Inhibitors Bearing Diverse Scaffolds.

ABSTRACT: In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure-activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple compounds, although there have been very few examples to follow such a policy. PI4KIII? is one of four mammalian phosphatidylinositol-4 kinases and has recently drawn significant attention as an emerging target for hepatitis C virus (HCV) treatment. In this letter, a novel "head-to-tail" approach to discover a diverse set of PI4KIII? inhibitors is reported. We believe this method will generate distinct core scaffolds, a rational strategy to circumvent potential risks in general kinase programs.

SUBMITTER: Noji S

PROVIDER: S-EPMC5066153 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Concise SAR Exploration Based on the "Head-to-Tail" Approach: Discovery of PI4KIIIα Inhibitors Bearing Diverse Scaffolds.

Noji Satoru S Seki Noriyoshi N Maeba Takaki T Sakai Takayuki T Watanabe Eiichi E Maeda Katsuya K Fukushima Kyoko K Noguchi Toru T Ogawa Kazuya K Toyonaga Yukiyo Y Negoro Tamotsu T Kawasaki Hisashi H Shiozaki Makoto M

ACS medicinal chemistry letters 20160803 10

In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure-activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple c ...[more]

PMID: 27774129

Dataset Information

Concise SAR Exploration Based on the "Head-to-Tail" Approach: Discovery of PI4KIII? Inhibitors Bearing Diverse Scaffolds.

Publications

Concise SAR Exploration Based on the "Head-to-Tail" Approach: Discovery of PI4KIIIα Inhibitors Bearing Diverse Scaffolds.

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