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Dive into the research topics where Surya K. De is active.

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Featured researches published by Surya K. De.


Proceedings of the National Academy of Sciences of the United States of America | 2008

Identification of a new JNK inhibitor targeting the JNK-JIP interaction site

John L. Stebbins; Surya K. De; Thomas Machleidt; Barbara Becattini; Jesús Vázquez; Christian Kuntzen; Li-Hsing Chen; Jason Cellitti; Megan Riel-Mehan; Aras Emdadi; Giovanni Solinas; Michael Karin; Maurizio Pellecchia

JNK is a stress-activated protein kinase that modulates pathways implicated in a variety of disease states. JNK-interacting protein-1 (JIP1) is a scaffolding protein that enhances JNK signaling by creating a proximity effect between JNK and upstream kinases. A minimal peptide region derived from JIP1 is able to inhibit JNK activity both in vitro and in cell. We report here a series of small molecules JIP1 mimics that function as substrate competitive inhibitors of JNK. One such compound, BI-78D3, dose-dependently inhibits the phosphorylation of JNK substrates both in vitro and in cell. In animal studies, BI-78D3 not only blocks JNK dependent Con A-induced liver damage but also restores insulin sensitivity in mouse models of type 2 diabetes. Our findings open the way for the development of protein kinase inhibitors targeting substrate specific docking sites, rather than the highly conserved ATP binding sites. In view of its favorable inhibition profile, selectivity, and ability to function in the cellular milieu and in vivo, BI-78D3 represents not only a JNK inhibitor, but also a promising stepping stone toward the development of an innovative class of therapeutics.


Journal of Medicinal Chemistry | 2009

Design, Synthesis, and Structure-Activity Relationship of Substrate Competitive, Selective, and in Vivo Active Triazole and Thiadiazole inhibitors of the c-Jun N-Terminal Kinase

Surya K. De; John L. Stebbins; Li-Hsing Chen; Megan Riel-Mehan; Thomas Machleidt; Russell Dahl; Hongbin Yuan; Aras Emdadi; Elisa Barile; Vida Chen; Ria Murphy; Maurizio Pellecchia

We report comprehensive structure-activity relationship studies on a novel series of c-Jun N-terminal kinase (JNK) inhibitors. The compounds are substrate competitive inhibitors that bind to the docking site of the kinase. The reported medicinal chemistry and structure-based optimizations studies resulted in the discovery of selective and potent thiadiazole JNK inhibitors that display promising in vivo activity in mouse models of insulin insensitivity.


PLOS ONE | 2012

Functional Specialization in Proline Biosynthesis of Melanoma

Jessica De Ingeniis; Boris I. Ratnikov; Adam D. Richardson; David A. Scott; Pedro Aza-Blanc; Surya K. De; Marat D. Kazanov; Maurizio Pellecchia; Ze'ev Ronai; Andrei L. Osterman; Jeffrey W. Smith

Proline metabolism is linked to hyperprolinemia, schizophrenia, cutis laxa, and cancer. In the latter case, tumor cells tend to rely on proline biosynthesis rather than salvage. Proline is synthesized from either glutamate or ornithine; both are converted to pyrroline-5-carboxylate (P5C), and then to proline via pyrroline-5-carboxylate reductases (PYCRs). Here, the role of three isozymic versions of PYCR was addressed in human melanoma cells by tracking the fate of 13C-labeled precursors. Based on these studies we conclude that PYCR1 and PYCR2, which are localized in the mitochondria, are primarily involved in conversion of glutamate to proline. PYCRL, localized in the cytosol, is exclusively linked to the conversion of ornithine to proline. This analysis provides the first clarification of the role of PYCRs to proline biosynthesis.


Chemical Biology & Drug Design | 2011

A disalicylic acid-furanyl derivative inhibits ephrin binding to a subset of Eph receptors.

Roberta Noberini; Surya K. De; Ziming Zhang; Bainan Wu; Dhanya Raveendra-Panickar; Vida Chen; Jesus Vazquez; Haina Qin; Jianxing Song; Nicholas D. P. Cosford; Maurizio Pellecchia; Elena B. Pasquale

Eph receptor tyrosine kinases and ephrin ligands control many physiological and pathological processes, and molecules interfering with their interaction are useful probes to elucidate their complex biological functions. Moreover, targeting Eph receptors might enable new strategies to inhibit cancer progression and pathological angiogenesis as well as promote nerve regeneration. Because our previous work suggested the importance of the salicylic acid group in antagonistic small molecules targeting Eph receptors, we screened a series of salicylic acid derivatives to identify novel Eph receptor antagonists. This identified a disalicylic acid‐furanyl derivative that inhibits ephrin‐A5 binding to EphA4 with an IC50 of 3 μm in ELISAs. This compound, which appears to bind to the ephrin‐binding pocket of EphA4, also targets several other Eph receptors. Furthermore, it inhibits EphA2 and EphA4 tyrosine phosphorylation in cells stimulated with ephrin while not affecting phosphorylation of EphB2, which is not a target receptor. In endothelial cells, the disalicylic acid‐furanyl derivative inhibits EphA2 phosphorylation in response to TNFα and capillary‐like tube formation on Matrigel, two effects that depend on EphA2 interaction with endogenous ephrin‐A1. These findings suggest that salicylic acid derivatives could be used as starting points to design new small molecule antagonists of Eph receptors.


Journal of Medicinal Chemistry | 2008

Development of Paramagnetic Probes for Molecular Recognition Studies in Protein Kinases

Jesus Vazquez; Surya K. De; Li-Hsing Chen; Megan Riel-Mehan; Aras Emdadi; Jason Cellitti; John L. Stebbins; Michele F. Rega; Maurizio Pellecchia

We report on the synthesis and evaluation of an indazole-spin-labeled compound that was designed as an effective chemical probe for second site screening against the protein kinase JNK using NMR-based techniques. We demonstrate the utility of the derived compound in detecting and characterizing binding events at the protein kinase docking site. In addition, we report on the NMR-based design and synthesis of a bidentate compound spanning both the ATP site and the docking site. We show that the resulting compound has nanomolar affinity for JNK despite the relatively weak affinities of the individual fragments that constitute it. The approach demonstrates that targeting the docking site of protein kinases represents a valuable yet unexplored avenue to obtain potent kinase inhibitors with increased selectivity.


Cancer Research | 2015

PDK1 and SGK3 contribute to the growth of BRAF mutant melanomas and are potential therapeutic targets

Marzia Scortegagna; Eric Lau; Tongwu Zhang; Yongmei Feng; Chris Sereduk; Hongwei Yin; Surya K. De; Katrina Meeth; James T. Platt; Casey G. Langdon; Ruth Halaban; Maurizio Pellecchia; Michael A. Davies; Kevin D. Brown; David F. Stern; Marcus Bosenberg; Ze'ev Ronai

Melanoma development involves members of the AGC kinase family, including AKT, PKC, and, most recently, PDK1, as elucidated recently in studies of Braf::Pten mutant melanomas. Here, we report that PDK1 contributes functionally to skin pigmentation and to the development of melanomas harboring a wild-type PTEN genotype, which occurs in about 70% of human melanomas. The PDK1 substrate SGK3 was determined to be an important mediator of PDK1 activities in melanoma cells. Genetic or pharmacologic inhibition of PDK1 and SGK3 attenuated melanoma growth by inducing G1 phase cell-cycle arrest. In a synthetic lethal screen, pan-PI3K inhibition synergized with PDK1 inhibition to suppress melanoma growth, suggesting that focused blockade of PDK1/PI3K signaling might offer a new therapeutic modality for wild-type PTEN tumors. We also noted that responsiveness to PDK1 inhibition associated with decreased expression of pigmentation genes and increased expression of cytokines and inflammatory genes, suggesting a method to stratify patients with melanoma for PDK1-based therapies. Overall, our work highlights the potential significance of PDK1 as a therapeutic target to improve melanoma treatment.


Bioorganic & Medicinal Chemistry | 2010

Synthesis and optimization of thiadiazole derivatives as a novel class of substrate competitive c-Jun N-terminal kinase inhibitors.

Surya K. De; Vida Chen; John L. Stebbins; Li-Hsing Chen; Jason Cellitti; Thomas Machleidt; Elisa Barile; Megan Riel-Mehan; Russell Dahl; Li Yang; Aras Emdadi; Ria Murphy; Maurizio Pellecchia

A series of thiadiazole derivatives has been designed as potential allosteric, substrate competitive inhibitors of the protein kinase JNK. We report on the synthesis, characterization and evaluation of a series of compounds that resulted in the identification of potent and selective JNK inhibitors targeting its JIP-1 docking site.


Chemistry & Biology | 2013

Structure-based design of covalent siah inhibitors.

John L. Stebbins; Eugenio Santelli; Yongmei Feng; Surya K. De; Angela Purves; Khatereh Motamedchaboki; Bainan Wu; Ze'ev Ronai; Robert C. Liddington; Maurizio Pellecchia

The E3 ubiquitin ligase Siah regulates key cellular events that are central to cancer development and progression. A promising route to Siah inhibition is disrupting its interactions with adaptor proteins. However, typical of protein-protein interactions, traditional unbiased approaches to ligand discovery did not produce viable hits against this target, despite considerable effort and a multitude of approaches. Ultimately, a rational structure-based design strategy was successful for the identification of Siah inhibitors in which peptide binding drives specific covalent bond formation with the target. X-ray crystallography, mass spectrometry, and functional data demonstrate that these peptide mimetics are efficient covalent inhibitors of Siah and antagonize Siah-dependent regulation of Erk and Hif signaling in the cell. The proposed strategy may result useful as a general approach to the design of peptide-based inhibitors of other protein-protein interactions.


Journal of Medicinal Chemistry | 2011

Design and characterization of a potent and selective dual ATP- and substrate-competitive subnanomolar bidentate c-Jun N-terminal kinase (JNK) inhibitor.

John L. Stebbins; Surya K. De; Petra Pavlickova; Vida Chen; Thomas Machleidt; Li-Hsing Chen; Christian Kuntzen; Shinichi Kitada; Michael Karin; Maurizio Pellecchia

c-Jun N-terminal kinases (JNKs) represent valuable targets in the development of new therapies. Present on the surface of JNK is a binding pocket for substrates and the scaffolding protein JIP1 in close proximity to the ATP binding pocket. We propose that bidentate compounds linking the binding energies of weakly interacting ATP and substrate mimetics could result in potent and selective JNK inhibitors. We describe here a bidentate molecule, 19, designed against JNK. 19 inhibits JNK kinase activity (IC(50) = 18 nM; K(i) = 1.5 nM) and JNK/substrate association in a displacement assay (IC(50) = 46 nM; K(i) = 2 nM). Our data demonstrate that 19 targets for the ATP and substrate-binding sites on JNK concurrently. Finally, compound 19 successfully inhibits JNK in a variety of cell-based experiments, as well as in vivo where it is shown to protect against Jo-2 induced liver damage and improve glucose tolerance in diabetic mice.


Bioorganic & Medicinal Chemistry | 2009

Discovery of 2-(5-nitrothiazol-2-ylthio)benzo[d]thiazoles as novel c-Jun N-terminal kinase inhibitors.

Surya K. De; Li-Hsing Chen; John L. Stebbins; Thomas Machleidt; Megan Riel-Mehan; Russell Dahl; Vida Chen; Hongbin Yuan; Elisa Barile; Aras Emdadi; Ria Murphy; Maurizio Pellecchia

A new series of 2-thioether-benzothiazoles has been synthesized and evaluated for JNK inhibition. The SAR studies led to the discovery of potent, allosteric JNK inhibitors with selectivity against p38.

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Aras Emdadi

University of California

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Paul B. Fisher

University of Alabama at Birmingham

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Bridget A. Quinn

Virginia Commonwealth University

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Hongwei Yin

Translational Genomics Research Institute

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Luni Emdad

Virginia Commonwealth University

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Michael A. Davies

University of Texas MD Anderson Cancer Center

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