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Biological and Medicinal Chemistry Approaches to Human Beta Cell Regeneration

人类 β 细胞再生的生物和药物化学方法

基本信息

批准号：
10580818
负责人：
Robert J DeVita
金额：
$ 62.99万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10580818
关键词：
Adult Adverse effects Affect Agonist Antibodies Automobile Driving Beta Cell Biochemistry Bromodeoxyuridine Cell Count Cell Differentiation process Cell Proliferation Cell surface Cells Chemicals Complement Coupling Data Development Diabetes Mellitus Drug Combinations Engraftment Family Focus Groups Future GCG gene Goals Hand Harmine Human In Vitro Individual Insulin Insulin-Dependent Diabetes Mellitus Label Lead Metabolic syndrome Modeling Monoclonal Antibodies NOD/SCID mouse National Institute of Diabetes and Digestive and Kidney Diseases Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Outcome Parents Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Physiological Population Prediabetes syndrome Process Proliferating Proliferation Marker Reproducibility Research Personnel Residual state Risk Safety Series Specificity Structure of beta Cell of islet System Therapeutic Transforming Growth Factor beta United States National Institutes of Health Withholding Treatment Work analog antibody conjugate antibody inhibitor cell regeneration chemical synthesis cost effective delivery vehicle diabetic euglycemia exenatide feasibility testing improved in vivo in vivo regeneration indexing inhibitor insight islet novel optimism prototype receptor regenerative regenerative cell regenerative therapy small molecule targeted delivery type I and type II diabetes

项目摘要

Both Type 1 and Type 2 diabetes (T1D and T2D) result from inadequate numbers of normally functioning beta cells. Small molecule drugs that inhibit the kinase, DYRK1A, such as harmine and others, are reproducibly able to induce adult human beta cells to replicate, but at low rates (~2%/day). More recently, we have shown that adding any small molecule DYRK1A inhibitor to either a TGF-beta superfamily inhibitor (TGFβI's) or to a GLP1 receptor agonist such as GLP1 or exendin-4 markedly enhances this replicative induction to rates averaging 5-8%/day. This has been documented not only by “markers” of replication such as Ki67 and BrdU, both in vitro and in vivo, but also by enhancing actual numbers of beta cells. Unfortunately, these drugs may not exclusively affect the beta cell, but instead may have “off target” effects as well. Thus, diabetes researchers have effective regenerative drugs to deliver to the human beta cell, but may require a “targeting molecule” to bring them to the beta cell. Accordingly, over the past few years, diabetes researchers have identified two classes of “prototype beta cell targeting molecules”: a monoclonal antibody raised against the beta cell surface molecule called “ENTPD3”; and, the GLP1-receptor class of molecules. While these molecules may or may not be perfect for beta cell targeting, they are unquestionably “prototype” targeting molecules with which to work while the field attempts to identify more perfect beta cell targeting molecules. We have also synthesized numerous DYRK1A inhibitors and TGFbeta inhibitors and cleavable chemical linkers that enable their conjugation to any potential beta cell targeting molecule. Thus, the Aims of this application are: 1. Synthesis of TGF-beta Inhibitors With Chemical Linkers, to Complement our Novel DYRK1A inhibitor Linker Compounds, For Conjugation To Prototype Targeted Delivery Vehicles. 2. Conjugation of Harmine-Linker and TGF-beta-Inhibitor-Linker Compounds to Two Prototype Targeting Molecules: GLP1 Receptor Agonists and ENTPD3 Monoclonal Antibodies. 3. Definition of Long Term Efficacy, Specificity and Safety of the Harmine-Linker and TGF-beta Inhibitor- Linker Conjugates in vivo in Human Islet Engraftment Models. These goals are both achievable and directly responsive to the goals of aims of the NIDDK. If GLP1 receptor agonists and/or ENTPD3 MAbs prove suboptimal for beta cell targeting, the approaches and molecules developed here can readily be extended and adapted to any future more specific human beta cell targeting molecule.

1型和2型糖尿病（T1D和T2D）都是由正常功能的β细胞数量不足引起的。抑制DYRK1A激酶的小分子药物，如毒碱和其他药物，可以诱导成人β细胞复制，但速率很低（~2%/天）。最近，我们已经证明，将任何小分子DYRK1A抑制剂添加到tgf - β超家族抑制剂（tgf - β i 's）或GLP1受体激动剂（如GLP1或exendin-4）中，可显著提高这种复制诱导率，平均为5-8%/天。这不仅通过体外和体内的Ki67和BrdU等复制“标记物”证明了这一点，而且还通过增加β细胞的实际数量证明了这一点。不幸的是，这些药物可能不仅影响β细胞，反而可能有“脱靶”效应。因此，糖尿病研究人员可以将有效的再生药物输送到人体β细胞，但可能需要一种“靶向分子”来将它们输送到β细胞。因此，在过去几年中，糖尿病研究人员已经确定了两类“原型β细胞靶向分子”：一种针对β细胞表面分子的单克隆抗体，称为“ENTPD3”；以及glp1受体类分子。虽然这些分子可能是也可能不是完美的β细胞靶向，但毫无疑问，它们是“原型”靶向分子，在该领域试图识别更完美的β细胞靶向分子时，它们可以发挥作用。我们还合成了许多DYRK1A抑制剂和TGFbeta抑制剂以及可切割的化学连接物，使它们能够与任何潜在的β细胞靶向分子结合。因此，此应用程序的目的是：1。带化学连接物的tgf - β抑制剂的合成，以补充我们的新型DYRK1A抑制剂连接物化合物，用于偶联到原型靶向递送载体。2 . hamine - linker和tgf -beta inhibitor - linker化合物与GLP1受体激动剂和ENTPD3单克隆抗体的偶联人体胰岛移植模型中hammin -连接子和tgf - β抑制剂-连接子偶联物的长期疗效、特异性和安全性的定义。这些目标既可以实现，又直接响应新千年发展框架的目标。如果GLP1受体激动剂和/或ENTPD3单克隆抗体被证明不是β细胞靶向的最佳选择，那么这里开发的方法和分子可以很容易地扩展和适应任何未来更特异性的人类β细胞靶向分子。