- Synthesis and biological evaluation of selected 7-azaindole derivatives as CDK9/Cyclin T and Haspin inhibitors
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The 7-azaindole scaffold attracts attention due to its value in the design of inhibitors of diseases related protein kinases. However, this scaffold has not been evaluated against Haploid germ cell-specific nuclear protein kinase (Haspin). Herein, we report the synthesis of a select set of 7-azaindole derivatives and their evaluation against Haspin. The compounds were also evaluated against CDK9/Cyclin T kinase. The synthesis of 7-azaindole derivatives was achieved through Suzuki coupling using appropriate halogenated 7-azaindole and boronic acids. Seven of the screened compounds exhibited activity as CDK9/Cyclin T and/or Haspin inhibitors in a nanomolar to low micromolar range. The most promising dual inhibiting compound 18c, exhibited an inhibitory potential of 0.206 μM against CDK9/Cyclin T and 0.118 μM against Haspin. The dual inhibition of CDK9/Cyclin T and Haspin could afford a potentially potent antimitotic agent of value in further anticancer studies.
- Pieterse, Lianie,Legoabe, Lesetja J.,Beteck, Richard M.,Josselin, Béatrice,Bach, Stéphane,Ruchaud, Sandrine
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p. 1449 - 1462
(2020/06/01)
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- Further modifications of 1H-pyrrolo[2,3-b]pyridine derivatives as inhibitors of human neutrophil elastase
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Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes and is considered to be a multifunctional enzyme. HNE is also involved in a variety of pathologies affecting the respiratory system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrrolo[2,3-b]pyridine derivatives of our previously reported potent HNE inhibitors. Our results show that position 2 of the pyrrolo[2,3-b]pyridine scaffold must be unsubstituted, and modifications of this position resulted in loss of HNE inhibitory activity. Conversely, the introduction of certain substituents at position 5 was tolerated, with retention of HNE inhibitory activity (IC50 = 15–51 nM) after most substitutions, indicating that bulky and/or lipophilic substituents at position 5 probably interact with the large pocket of the enzyme site and allow Michaelis complex formation. The possibility of Michaelis complex formation between Ser195 and the ligand carbonyl group was assessed by molecular docking, and it was found that highly active HNE inhibitors are characterized by geometries favorable for Michaelis complex formation and by relatively short lengths of the proton transfer channel via the catalytic triad.
- Giovannoni, Maria P.,Cantini, Niccolò,Crocetti, Letizia,Guerrini, Gabriella,Iacovone, Antonella,Schepetkin, Igor A.,Vergelli, Claudia,Khlebnikov, Andrei I.,Quinn, Mark T.
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p. 617 - 628
(2019/04/30)
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- Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations
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The use of covalent irreversible binding inhibitors is an established concept for drug development. Usually, the discovery of new irreversible kinase inhibitors occurs serendipitously, showing that efficient rational approaches for the rapid discovery of new drugs are needed. Herein, we report a virtual screening strategy that led to the discovery of irreversible inhibitors of FMS-like tyrosine kinase 3 (FLT3) involved in the pathogenesis of acute myeloid leukemia. A virtual screening library was designed to target the highly conserved Cys828 residue preceding the DFG motif by modification of reported reversible inhibitors with chemically reactive groups. Prospective covalent docking allowed the identification of two lead series, resulting in a massive increase in inhibition of kinase activity and cell viability by irreversible inhibitors compared to the corresponding reversible scaffolds. Lead compound 4b (BSc5371) displays superior cytotoxicity in FLT3-dependent cell lines to compounds in recent clinical trials and overcomes drug-resistant mutations.
- Bensinger, Dennis,Stubba, Daniel,Cremer, Anjali,Kohl, Vanessa,Wa?mer, Theresa,Stuckert, Johanna,Engemann, Victoria,Stegmaier, Kimberly,Schmitz, Katja,Schmidt, Boris
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supporting information
p. 2428 - 2446
(2019/03/11)
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- A novel protocol for the one-pot borylation/Suzuki reaction provides easy access to hinge-binding groups for kinase inhibitors
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The one-pot borylation/Suzuki reaction is a very efficient means of accessing cross-coupling products of two aryl-halide partners that generally requires the use of specific catalysts or ligands and/or relatively long reaction times. This new microwave-assisted method provides a quick one-pot borylation/Suzuki reaction protocol that we applied to the synthesis of various bi- or poly-aryl scaffolds, including a variety of aryl and heteroaryl ring systems and the core frameworks of kinase inhibitors vemurafenib and GDC-0879.
- Hooper,Zambon,Springer
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p. 963 - 969
(2016/01/15)
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- Discovery of small molecule RIP1 kinase inhibitors for the treatment of pathologies associated with necroptosis
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Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house ki
- Harris, Philip A.,Bandyopadhyay, Deepak,Berger, Scott B.,Campobasso, Nino,Capriotti, Carol A.,Cox, Julie A.,Dare, Lauren,Finger, Joshua N.,Hoffman, Sandra J.,Kahler, Kirsten M.,Lehr, Ruth,Lich, John D.,Nagilla, Rakesh,Nolte, Robert T.,Ouellette, Michael T.,Pao, Christina S.,Schaeffer, Michelle C.,Smallwood, Angela,Sun, Helen H.,Swift, Barbara A.,Totoritis, Rachel D.,Ward, Paris,Marquis, Robert W.,Bertin, John,Gough, Peter J.
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supporting information
p. 1238 - 1243
(2014/01/06)
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- Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors
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The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in par
- Hammond, Marlys,Washburn, David G.,Hoang, Tram H.,Manns, Sharada,Frazee, James S.,Nakamura, Hiroko,Patterson, Jaclyn R.,Trizna, Walter,Wu, Charlene,Azzarano, Leonard M.,Nagilla, Rakesh,Nord, Melanie,Trejo, Rebecca,Head, Martha S.,Zhao, Baoguang,Smallwood, Angela M.,Hightower, Kendra,Laping, Nicholas J.,Schnackenberg, Christine G.,Thompson, Scott K.
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experimental part
p. 4441 - 4445
(2010/04/05)
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- 1H-PYRROLO[2,3-B]PYRIDINES
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Derivatives of pyrrolo[2,3-b]pyridine which are useful as SGK-1 kinase inhibitors are described herein. The invention described herein also describes pharmaceutical compositions containing derivatives of pyrrolo[2,3-b]pyridine and methods of using pyrrolo[2,3-b]pyridine derivatives and pharmaceutical compositions thereof in the treatment of diseases mediated by SGK-1.
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Page/Page column 18; 34
(2008/06/13)
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