Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity in Vivo Mouse Model.,Journal of Medicinal Chemistry

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Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity in Vivo Mouse Model.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-05-20 , DOI: 10.1021/acs.jmedchem.9b01803
Christophe Fromont ₁ , Alessio Atzori ₁ , Divneet Kaur ₁ , Lubna Hashmi ₁ , Graziella Greco ₂ , Alejandro Cabanillas ₂ , Huy Van Nguyen ₂ , D Heulyn Jones ₃ , Miguel Garzón ₃ , Ana Varela ₃ , Brett Stevenson ₄ , Greg P Iacobini ₄ , Marc Lenoir ₅ , Sundaresan Rajesh ₅ , Clare Box ₅ , Jitendra Kumar ₆ , Paige Grant ₆ , Vera Novitskaya ₅ , Juliet Morgan ₄ , Fiona J Sorrell ₇ , Clara Redondo ₇ , Andreas Kramer ₈ , C John Harris ₉ , Brendan Leighton ₁₀ , Steven P Vickers ₁₁ , Sharon C Cheetham ₁₁ , Colin Kenyon ₁₂ , Anna M Grabowska ₁₃ , Michael Overduin ₆ , Fedor Berditchevski ₅ , Chris J Weston _{14,

15} , Stefan Knapp ₈ , Peter M Fischer ₁ , Sam Butterworth ₃

Affiliation

Centre for Biomolecular Sciences and School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, U.K.
School of Pharmacy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston B15 2TT, U.K.
Division of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PL, U.K.
Sygnature Discovery, BioCity, Pennyfoot Street, Nottingham NG1 1GF, U.K.
Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, U.K.
Structural Genomics Consortium and Buchmann Institute for Molecular Life Sciences, Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany.
CJH Consultants, Ford Cottage, South Weirs, Burley Road, Brockenhurst, Hants SO42 7UQ, U.K.
The Research Network, IPC 600 Discovery Park, Ramsgate Road, Sandwich CT13 9NJ, U.K.
RenaSci Limited, BioCity, Pennyfoot Street, Nottingham NG1 1GF, U.K.
DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, SAMRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 8000, South Africa.
Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2RD, U.K.
Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TT, U.K.
NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, B15 2TT, U.K.

Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as in vivo tool compounds. Our results show that a lead compound from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.

中文翻译：

钙调蛋白依赖性激酶的高度选择性抑制剂的发现，该抑制剂可在体内小鼠模型中的饮食诱导型肥胖中恢复胰岛素敏感性。

钙调蛋白依赖性激酶同工型D（CaMK1D）基因区域中的多态性与糖尿病的发生率增加有关，最常见的多态性导致转录因子的识别增加和蛋白质表达增加。尽管降低CaMK1D表达对人肝细胞中的葡萄糖加工具有潜在的有益作用，但尚无已知的CaMK1激酶选择性抑制剂可用于验证或翻译这些发现。在这里，我们描述了一系列有效的，选择性的和药物样的CaMK1抑制剂的开发，这些抑制剂能够在小鼠模型中提供显着的游离靶标覆盖，因此可在体内使用工具化合物。我们的结果表明，该系列的先导化合物在急性和慢性给药后均可改善饮食诱发的肥胖小鼠模型中的胰岛素敏感性和血糖控制，从而首次将CaMK1D作为糖尿病治疗的靶标进行了体内验证。

更新日期：2020-07-09

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