Abstract
Compound 1, a hit from the screening of our chemical collection displaying activity against JAK2, was deconstructed for SAR analysis into three regions, which were explored. A series of compounds was synthesized leading to the identification of the potent and orally bioavailable JAK2 inhibitor 16 (NMS-P830), which showed an encouraging tumour growth inhibition in SET-2 xenograft tumour model, with evidence for JAK2 pathway suppression demonstrated by in vivo pharmacodynamic effects.
Keywords:
Anti-cancer agents; JAK2; Myeloproliferative disorders; Protein kinase inhibitor; Tumour cell proliferation inhibition.
Copyright © 2015 Elsevier Ltd. All rights reserved.
MeSH terms
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Amides / chemical synthesis*
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Amides / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Female
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Gene Expression
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High-Throughput Screening Assays
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Humans
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Janus Kinase 2 / antagonists & inhibitors*
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Janus Kinase 2 / chemistry
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Janus Kinase 2 / genetics
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Janus Kinase 2 / metabolism
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Leukemia, Megakaryoblastic, Acute / drug therapy*
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Leukemia, Megakaryoblastic, Acute / enzymology
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Leukemia, Megakaryoblastic, Acute / genetics
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Leukemia, Megakaryoblastic, Acute / pathology
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Megakaryocyte Progenitor Cells / drug effects
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Megakaryocyte Progenitor Cells / enzymology
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Megakaryocyte Progenitor Cells / pathology
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Mice
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Mice, Nude
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Molecular Docking Simulation
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Molecular Dynamics Simulation
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacology
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Amides
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyrroles
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JAK2 protein, human
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Janus Kinase 2