Design of potent thiophene inhibitors of polo-like kinase 1 with improved solubility and reduced protein binding

Emmitte, Kyle A.; Adjebang, George M.; Andrews, Chandler; Alberti, Jennifer G. Badiang; Bambal, Ramesh; Chamberlain, Stanley D.; Davis‐Ward, Ronda G.; Dickson, Hamilton D.; Hassler, Daniel F.; Hornberger, Keith R.; Jackson, Jeffrey R.; Kuntz, Kevin W.; Lansing, Timothy J.; Mook, Robert A.; Nailor, Kristen E.; Pobanz, Mark A.; Smith, Stephon C.; Sung, Chiu Mei; Cheung, Mui

doi:10.1016/j.bmcl.2009.01.094

Cited by 56 publications

(50 citation statements)

References 13 publications

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“…34, 35 A main focus of Plk1 inhibitor development has been directed at the kinase catalytic domain. 36–43 However, Plk1 contains modular C-terminal “Polo-box domains” (PBDs) that bind specific phosphoserine and phosphothreonine-containing sequences to provide critical localization of Plk1. 32, 44, 45 Competitive PBD binding antagonists could serve as inhibitors of Plk1 function that are distinct from kinase-directed agents.…”

Section: Application Of Reagent 4 To the Synthesis Of Polo Box Domainmentioning

confidence: 99%

Preparation of orthogonally protected (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) as a phosphatase-stable phosphothreonine mimetic and its use in the synthesis of polo-box domain-binding peptides

et al. 2009

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Reported herein is the first stereoselective synthesis of (2S,3R)-4-[bis-(tert-butyloxy)phosphinyl]-2-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-3-methylbutanoic acid [(N-Fmoc, O,O-(bis-(tert-butyl))-Pmab, 4] as a hydrolytically-stable phosphothreonine mimetic bearing orthogonal protection compatible with standard solid-phase protocols. The synthetic approach used employs Evans’ oxazolidinone for chiral induction. Also presented is the application of 4 in the solid-phase synthesis of polo-like kinase 1 (Plk1) polo box domain (PBD)-binding peptides. These Pmab-containing peptides retain PBD binding efficacy similar to a parent pThr containing peptide. Reagent 4 should be a highly useful reagent for the preparation of signal transduction-directed peptides.

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Section: Application Of Reagent 4 To the Synthesis Of Polo Box Domainmentioning

confidence: 99%

Preparation of orthogonally protected (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) as a phosphatase-stable phosphothreonine mimetic and its use in the synthesis of polo-box domain-binding peptides

et al. 2009

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“…Interestingly, the docking studies with an analogue of GSK461364A reveal that the basic nitrogens pointing to cavity may interact with Glu140. Although it is not understood whether this interaction is critical for delivering kinase selectivity, both Plk2 and Plk3 possess a His residue at the position analogous to that of Glu140 in Plk1, and therefore fail to generate favorable salt-bridge interaction (Emmitte et al, 2009). While the observed selectivity is yet to be further validated, this GSK461364A is broadly active against several hundred tumor cell lines with proliferation IC 50 values of < 100 nM in 91% of all cell lines examined.…”

Section: Gsk461364amentioning

confidence: 99%

Plk1-Targeted Small Molecule Inhibitors: Molecular Basis for Their Potency and Specificity

Murugan

Park

Kim

et al. 2011

Molecules and Cells

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“…Although a small molecule inhibitor of the interaction of Hec1 with Nek2 has been described(18) and a Plk1 inhibitor 1 has been shown to have Nek2 activity in a counterscreen (Figure 1),(19) no systematic investigation of Nek2 inhibitors has been disclosed to our knowledge. We herein report the exploration of a series of pyrazine-based Nek2 inhibitors identified through high-throughput screening (HTS).…”

Section: Introductionmentioning

confidence: 99%

Aminopyrazine Inhibitors Binding to an Unusual Inactive Conformation of the Mitotic Kinase Nek2: SAR and Structural Characterization

et al. 2010

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We report herein the first systematic exploration of inhibitors of the mitotic kinase Nek2. Starting from HTS hit aminopyrazine 2, compounds with improved activity were identified using structure-based design. Our structural biology investigations reveal two notable observations. First, 2 and related compounds bind to an unusual, inactive conformation of the kinase which to the best of our knowledge has not been reported for other types of kinase inhibitors. Second, a phenylalanine residue at the center of the ATP pocket strongly affects the ability of the inhibitor to bind to the protein. The implications of these observations are discussed, and the work described here defines key features for potent and selective Nek2 inhibition, which will aid the identification of more advanced inhibitors of Nek2.

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Design of potent thiophene inhibitors of polo-like kinase 1 with improved solubility and reduced protein binding

Cited by 56 publications

References 13 publications

Preparation of orthogonally protected (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) as a phosphatase-stable phosphothreonine mimetic and its use in the synthesis of polo-box domain-binding peptides

Preparation of orthogonally protected (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) as a phosphatase-stable phosphothreonine mimetic and its use in the synthesis of polo-box domain-binding peptides

Plk1-Targeted Small Molecule Inhibitors: Molecular Basis for Their Potency and Specificity

Aminopyrazine Inhibitors Binding to an Unusual Inactive Conformation of the Mitotic Kinase Nek2: SAR and Structural Characterization

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