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从靶标内到靶标外活性：鉴定和优化布氏锥虫 GSK3 抑制剂及其作为抗布氏锥虫药物发现先导分子的特征。

From on-target to off-target activity: identification and optimisation of Trypanosoma brucei GSK3 inhibitors and their characterisation as anti-Trypanosoma brucei drug discovery lead molecules.

机构信息

Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, DD1 5EH, UK.

出版信息

ChemMedChem. 2013 Jul;8(7):1127-37. doi: 10.1002/cmdc.201300072. Epub 2013 Jun 14.

DOI:10.1002/cmdc.201300072
PMID:23776181
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3728731/
Abstract

Human African trypanosomiasis (HAT) is a life-threatening disease with approximately 30 000-40 000 new cases each year. Trypanosoma brucei protein kinase GSK3 short (TbGSK3) is required for parasite growth and survival. Herein we report a screen of a focused kinase library against T. brucei GSK3. From this we identified a series of several highly ligand-efficient TbGSK3 inhibitors. Following the hit validation process, we optimised a series of diaminothiazoles, identifying low-nanomolar inhibitors of TbGSK3 that are potent in vitro inhibitors of T. brucei proliferation. We show that the TbGSK3 pharmacophore overlaps with that of one or more additional molecular targets.

摘要

人类非洲锥虫病（HAT）是一种危及生命的疾病，每年约有 30000-40000 例新发病例。布氏锥虫蛋白激酶 GSK3 短（TbGSK3）是寄生虫生长和存活所必需的。本文报道了针对 T. brucei GSK3 的靶向激酶文库筛选。从中我们鉴定出一系列具有高配体效率的 TbGSK3 抑制剂。在进行命中验证后，我们对一系列二氨基噻唑进行了优化，鉴定出了对 TbGSK3 具有低纳摩尔抑制活性的抑制剂，对 T. brucei 的增殖具有很强的抑制作用。我们表明，TbGSK3 的药效团与一个或多个其他分子靶标重叠。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/5fad999a9a4b/cmdc0008-1127-f9.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/19e811f72186/cmdc0008-1127-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/328142ea5c36/cmdc0008-1127-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/5fad999a9a4b/cmdc0008-1127-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/29c5d746bb4a/cmdc0008-1127-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/093359cffe30/cmdc0008-1127-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/7c35f97ca866/cmdc0008-1127-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/c6decf4a9d92/cmdc0008-1127-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/ef57ea4847e8/cmdc0008-1127-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/8b29917396f2/cmdc0008-1127-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/a82a4de77941/cmdc0008-1127-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/19e811f72186/cmdc0008-1127-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/328142ea5c36/cmdc0008-1127-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63a4/3728731/5fad999a9a4b/cmdc0008-1127-f9.jpg

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