Discovery of novel isothiazole inhibitors of the TrkA kinase: Structure–activity relationship, computer modeling, optimization, and identification of highly potent antagonists

Lippa, Blaise; Morris, Joel; Corbett, Matthew S.; Kwan, Tricia A.; Noe, Mark C.; Snow, Sheri L.; Gant, Thomas G.; Mangiaracina, Melchiorra; Coffey, Heather; Foster, Barbara A.; Knauth, Elisabeth; Wessel, Matthew D.

doi:10.1016/j.bmcl.2006.04.003

Cited by 46 publications

(17 citation statements)

References 11 publications

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“…Compound 1 is a representative of the dual-inhibitor class on the basis of its dual actions towards both the ATP and JIP sites, but probably binding in the ATP site on the basis of the loss of JIP-JNK inhibition in an excess of ATP and on its predicted binding mode. In a study by Lippa et al [32], closely related analogues of compound 1 were docked to the ATP site. Compound 2 belongs to the polychloropyrimidine series and is characterized as a potential JIP-site binder.…”

Section: Characterization Of Lead Seriesmentioning

confidence: 99%

Identification of small-molecule inhibitors of the JIP–JNK interaction

Chen

Kablaoui

Little

et al. 2009

Biochemical Journal

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JNK1 (c-Jun N-terminal kinase 1) plays a crucial role in the regulation of obesity-induced insulin resistance and is implicated in the pathology of Type 2 diabetes. Its partner, JIP1 (JNK-interacting protein 1), serves a scaffolding function that facilitates JNK1 activation by MKK4 [MAPK (mitogen-activated protein kinase) kinase 4] and MKK7 (MAPK kinase 7). For example, reduced insulin resistance and JNK activation are observed in JIP1-deficient mice. On the basis of the in vivo efficacy of a cell-permeable JIP peptide, the JIP-JNK interaction appears to be a potential target for JNK inhibition. The goal of the present study was to identify small-molecule inhibitors that disrupt the JIP-JNK interaction to provide an alternative approach for JNK inhibition to ATP-competitive inhibitors. High-throughput screening was performed by utilizing a fluorescence polarization assay that measured the binding of JNK1 to the JIP peptide. Multiple chemical series were identified, revealing two categories of JIP/JNK inhibitors: 'dual inhibitors' that are ATP competitive and probably inhibit JIP-JNK binding allosterically, and 'JIP-site binders' that block binding through interaction with the JIP site. A series of polychloropyrimidines from the second category was characterized by biochemical methods and explored through medicinal-chemistry efforts. As predicted, these inhibitors also inhibited full-length JIP-JNK binding and were selective against a panel of 34 representative kinases, including ones in the MAPK family. Overall, this work demonstrates that small molecules can inhibit protein-protein interactions in vitro in the MAPK family effectively and provides strategies for similar approaches within other target families.

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Section: Characterization Of Lead Seriesmentioning

confidence: 99%

Identification of small-molecule inhibitors of the JIP–JNK interaction

Chen

Kablaoui

Little

et al. 2009

Biochemical Journal

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“…In the past, small molecule kinase inhibitors, such as K252a [16,17] and the isothiazole family of compounds [18], have functionally limited TrkA signalling in experimental models, but their partial specificity has prevented clinical translation. An alternative strategy which shows much promise is the use of therapeutic biologicals.…”

Section: Discussionmentioning

confidence: 99%

Affinity Crosslinking of Y1036 to Nerve Growth Factor Identifies Pharmacological Targeting Domain for Small Molecule Neurotrophin Antagonists

Eibl¹,

Abdallah²,

Kennedy³

et al. 2013

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Classically, small molecule antagonists have targeted membrane bound receptors and intracellular enzyme targets. While this drug discovery strategy is extremely successful, the number of new chemical entities in the pharmaceutical pipeline is diminishing and complementary strategies are in need. A particularly attractive therapeutic strategy is to neutralize soluble signalling proteins using small molecules. Small molecule-based technologies have the potential to sufficiently alter the molecular topology of a given ligand and inhibit ligand/receptor interactions-effectively neutralizing the ligand's signalling capacity. Recent technical advances in the field of structural biology have enabled the elucidation of ligand/receptor complexes at atomic resolution enabling a detailed appreciation of the molecular interactions governing ligand-mediated receptor activation. Exploiting molecular modeling techniques to study these signalling complexes allows for a paradigm shift from "receptorcentric" to "ligandcentric" screening strategies. Nerve growth factor (NGF) is a prototypical protein signalling ligand, which binds two receptors, TrkA and p75 NTR . We first explore the molecular landscape governing the ligand/receptor interactions of NGF/TrkA and NGF/p75 structures. Next, we use the recently reported NGF neutralizing small-molecule, Y1036, as an affinity probe to determine residues in proximity to the pharmacological targeting domain of NGF and perform theoretical docking experiments to predict the residues which comprise distinct pharmacological targeting domains on the surface of NGF. Exploiting such strategies may facilitate "ligandcentric" drug discovery and could further the development of a trophic-factor-selective compound such as a BDNF-selective antagonist.

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“…Researchers from Pfizer reported a series of isothiazole derivatives as potent TrkA inhibitors in 2006 [104]. A high-throughput screening effort uncovered the substituted isothiazole 11 as a lead with an IC 50 values of 7 nM and 300nM against TrkA kinase and TrkA cell-based studies, respectively (Figure 8).…”

Section: Discovery Of the Trka Inhibitors Isothiazole 14 And Az-23mentioning

confidence: 99%

Chiral Kinase Inhibitors

Jiang

Shen²,

Thomas³

et al. 2011

CTMC

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Small molecule kinase inhibitors are important tools for studying cellular signaling pathways, phenotypes and are, occasionally, useful clinical agents. With stereochemistry pervasive throughout the molecules of life it is no surprise that a single stereocenter can bestow a ligand with distinct binding affinities to various protein targets. While the majority of small molecule kinase inhibitors reported to date are achiral, a number of asymmetric compounds show great utility as tools for probing kinase-associated biomolecular events as well as promising therapeutic leads. The mechanism by which chirality is introduced varies but includes screening of chiral libraries, incorporation of chiral centers during optimization efforts and the rational installation of a chiral moiety as guided by structural and modeling efforts. Here we discuss several advanced chiral small molecule kinase inhibitors where stereochemistry plays an important role in terms of potency and selectivity.

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Discovery of novel isothiazole inhibitors of the TrkA kinase: Structure–activity relationship, computer modeling, optimization, and identification of highly potent antagonists

Cited by 46 publications

References 11 publications

Identification of small-molecule inhibitors of the JIP–JNK interaction

Identification of small-molecule inhibitors of the JIP–JNK interaction

Affinity Crosslinking of Y1036 to Nerve Growth Factor Identifies Pharmacological Targeting Domain for Small Molecule Neurotrophin Antagonists

Chiral Kinase Inhibitors

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