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Your search keyword '"Fan, Junhua"' showing total 4 results
Start Over Author "Fan, Junhua" Topic protein kinase inhibitors
4 results on '"Fan, Junhua"'

1. Structure-based design of low-nanomolar PIM kinase inhibitors.

Author

Ishchenko A, Zhang L, Le Brazidec JY, Fan J, Chong JH, Hingway A, Raditsis A, Singh L, Elenbaas B, Hong VS, Marcotte D, Silvian L, Enyedy I, and Chao J

Subjects
Binding Sites, Crystallography, X-Ray, Hydrogen Bonding, Molecular Dynamics Simulation, Protein Binding, Protein Isoforms antagonists & inhibitors, Protein Isoforms metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors metabolism, Protein Structure, Tertiary, Proto-Oncogene Proteins c-pim-1 metabolism, Static Electricity, Structure-Activity Relationship, Drug Design, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors
Abstract

PIM kinases are implicated in variety of cancers by promoting cell survival and proliferation and are targets of interest for therapeutic intervention. We have identified a low-nanomolar pan-PIM inhibitor (PIM1/2/3 potency 5:14:2nM) using structure based modeling. The crystal structure of this compound with PIM1 confirmed the predicted binding mode and protein-ligand interactions except those in the acidic ribose pocket. We show the SAR suggesting the importance of having a hydrogen bond donor in this pocket for inhibiting PIM2; however, this interaction is not important for inhibiting PIM1 or PIM3. In addition, we report the discovery of a new class of PIM inhibitors by using computational de novo design tool implemented in MOE software (Chemical Computing Group). These inhibitors have a different interaction profile., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2015
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2. Structure-based design of 2,6,7-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines as Aurora kinases inhibitors.

Author

Le Brazidec JY, Pasis A, Tam B, Boykin C, Wang D, Marcotte DJ, Claassen G, Chong JH, Chao J, Fan J, Nguyen K, Silvian L, Ling L, Zhang L, Choi M, Teng M, Pathan N, Zhao S, Li T, and Taveras A

Subjects
Antineoplastic Agents pharmacology, Aurora Kinases, Binding Sites, Cell Cycle Checkpoints drug effects, Cell Line, Drug Design, Humans, Models, Molecular, Molecular Structure, Protein Binding, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases chemistry, Pyrimidines pharmacology, Pyrroles pharmacology, Structural Homology, Protein, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, CDC2 Protein Kinase chemistry, Cyclin-Dependent Kinase 2 chemistry, Protein Kinase Inhibitors chemical synthesis, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrimidines chemical synthesis, Pyrroles chemical synthesis
Abstract

This Letter reports the optimization of a pyrrolopyrimidine series as dual inhibitors of Aurora A/B kinases. This series derived from a pyrazolopyrimidine series previously reported as inhibitors of aurora kinases and CDKs. In an effort to improve the selectivity of this chemotype, we switched to the pyrrolopyrimidine core which allowed functionalization on C-2. In addition, the modeling rationale was based on superimposing the structures of Aurora-A kinase and CDK2 which revealed enough differences leading to a path for selectivity improvement. The synthesis of the new series of pyrrolopyrimidine analogs relied on the development of a different route for the two key intermediates 7 and 19 which led to analogs with both tunable activity against CDK1 and maintained cell potency., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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3. Synthesis, SAR and biological evaluation of 1,6-disubstituted-1H-pyrazolo[3,4-d]pyrimidines as dual inhibitors of Aurora kinases and CDK1.

Author

Le Brazidec JY, Pasis A, Tam B, Boykin C, Black C, Wang D, Claassen G, Chong JH, Chao J, Fan J, Nguyen K, Silvian L, Ling L, Zhang L, Choi M, Teng M, Pathan N, Zhao S, Li T, and Taveras A

Subjects
Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Aurora Kinase A, Aurora Kinase B, Aurora Kinases, CDC2 Protein Kinase metabolism, Cell Line, Colon drug effects, Colon pathology, Colonic Neoplasms pathology, HCT116 Cells, Humans, Mice, Models, Molecular, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases metabolism, Pyrazoles chemistry, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyrazoles therapeutic use, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Rats, Structure-Activity Relationship, CDC2 Protein Kinase antagonists & inhibitors, Colonic Neoplasms drug therapy, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors therapeutic use, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrimidines chemistry, Pyrimidines therapeutic use
Abstract

Since the early 2000s, the Aurora kinases have become major targets of oncology drug discovery particularly Aurora-A and Aurora-B kinases (AKA/AKB) for which the selective inhibition in cells lead to different phenotypes. In addition to targeting these Aurora kinases involved in mitosis, CDK1 has been added as a primary inhibition target in hopes of enhancing the cytotoxicity of our chemotypes harboring the pyrazolopyrimidine core. SAR optimization of this series using the AKA, AKB and CDK1 biochemical assays led to the discovery of the compound 7h which combines strong potency against the 3 kinases with an acceptable microsomal stability. Finally, switching from a primary amide to a two-substituted pyrrolidine amide gave rise to compound 15a which exhibited the desired AKA/CDK1 inhibition phenotype in cells but showed moderate activity in animal models using HCT116 tumor cell lines., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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4. Design, synthesis, and biological evaluation of pyrazolopyrimidine-sulfonamides as potent multiple-mitotic kinase (MMK) inhibitors (part I).

Author

Zhang L, Fan J, Chong JH, Cesena A, Tam BY, Gilson C, Boykin C, Wang D, Aivazian D, Marcotte D, Xiao G, Le Brazidec JY, Piao J, Lundgren K, Hong K, Vu K, Nguyen K, Gan LS, Silvian L, Ling L, Teng M, Reff M, Takeda N, Timple N, Wang Q, Morena R, Khan S, Zhao S, Li T, Lee WC, Taveras AG, and Chao J

Subjects
Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Aurora Kinase A, Aurora Kinases, CDC2 Protein Kinase metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Chemistry Techniques, Synthetic, Colonic Neoplasms pathology, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Design, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Humans, Mice, Mice, Nude, Models, Molecular, Molecular Structure, Neoplasms, Experimental drug therapy, Neoplasms, Experimental pathology, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases metabolism, Pyrimidines chemical synthesis, Pyrimidines chemistry, Stereoisomerism, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides chemistry, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, CDC2 Protein Kinase antagonists & inhibitors, Colonic Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrimidines pharmacology, Sulfonamides pharmacology
Abstract

A novel class of pyrazolopyrimidine-sulfonamides was discovered as selective dual inhibitors of aurora kinase A (AKA) and cyclin-dependent kinase 1 (CDK1). These inhibitors were originally designed based on an early lead (compound I). SAR development has led to the discovery of potent inhibitors with single digit nM IC(50)s towards both AKA and CDK1. An exemplary compound 1a has demonstrated good efficacy in an HCT116 colon cancer xenograft model., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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