- 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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- Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent in Vitro and in Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model
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In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ~33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.
- Singh, Umed,Chashoo, Gousia,Khan, Sameer U.,Mahajan, Priya,Nargotra, Amit,Mahajan, Girish,Singh, Amarinder,Sharma, Anjna,Mintoo, Mubashir J.,Guru, Santosh Kumar,Aruri, Hariprasad,Thatikonda, Thanusha,Sahu, Promod,Chibber, Pankaj,Kumar, Vikas,Mir, Sameer A.,Bharate, Sonali S.,Madishetti, Sreedhar,Nandi, Utpal,Singh, Gurdarshan,Mondhe, Dilip Manikrao,Bhushan, Shashi,Malik, Fayaz,Mignani, Serge,Vishwakarma, Ram A.,Singh, Parvinder Pal
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p. 9470 - 9489
(2017/12/26)
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- NOVEL AZAINDOLE DERIVATIVES AS SELECTIVE HISTONE DEACETYLASE (HDAC) INHIBITORS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME
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The present invention relates to novel azaindole derivatives, and more particularly, to novel azaindole derivatives having histone deacetylase (HDAC) inhibitory activity, isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof or solvates thereof, the use thereof for the preparation of pharmaceutical compositions, pharmaceutical compositions containing the same, a method of treating disease using the pharmaceutical compositions, and methods for preparing the novel azaindole derivatives. The novel azaindole derivatives according to the present invention are selective histone deacetylase (HDAC) inhibitors, and may be used as agents for treating malignant tumor diseases, inflammatory diseases, rheumatoid arthritis, and neurodegenerative diseases.
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Paragraph 251; 252; 253
(2015/06/25)
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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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- COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR
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Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.
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Page/Page column 37-38
(2008/12/06)
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- COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR
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Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.
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Page/Page column 60
(2008/12/07)
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- PYRROLO[2,3-B] PYRIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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Compounds of formula III which are active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.
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Page/Page column 123
(2010/11/25)
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