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：
10363716
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/10363716
关键词：
Adult Adverse effects Affect Agonist Antibodies Automobile Driving Beta Cell Biochemistry Bromodeoxyuridine Cell Count Cell Differentiation process Cell Proliferation Cell surface 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 Proliferation Marker Research Personnel Residual state Risk Safety Series Specificity Structure of beta Cell of islet System Therapeutic Transforming Growth Factor alpha Transforming Growth Factor beta United States National Institutes of Health Withholding Treatment Work analog antibody conjugate antibody inhibitor base cell regeneration chemical synthesis cost effective delivery vehicle diabetic exenatide feasibility testing improved in vivo indexing inhibitor insight islet novel optimism prototype receptor regenerative regenerative cell regenerative therapy small molecule targeted delivery

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.

类型1和2型糖尿病（T1D和T2D）都是由正常运行的β细胞数量不足所致。抑制激酶DYRK1A（例如Harmine等）的小分子药物可重复地诱导成年人类β细胞复制，但以较低的速度（约2％/天）。最近，我们表明，将任何小分子dyRK1a抑制剂添加到TGF-beta超家族抑制剂（TGFβI）或GLP1接收器激动剂（例如GLP1或Exendin-4）中，显着增强了这种复制诱导，以增强该复制性诱导率，以平均5-8％/天。这不仅是通过在体外和体内的复制的“标记”（例如Ki67和Brdu）所记录的，而且还通过增强实际数量的β细胞数量来证明这一点。不幸的是，这些药物可能不会仅仅影响β细胞，而是可能会产生“关闭目标”的影响。这是糖尿病研究人员具有有效的再生药物来传递到人β细胞的，但可能需要“靶向分子”将其带入β细胞。彼此之间，在过去的几年中，糖尿病研究人员确定了两类的“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”；并且，GLP1受体分子类别。尽管这些分子对于β细胞的靶向可能是理想的，也可能不是完美的，但毫无疑问，它们可以“原型”靶向分子，而该域则试图识别更完美的β细胞靶向分子。我们还合成了许多DYRK1A抑制剂和TGFBETA抑制剂和可裂解的化学接头，使它们能够与任何潜在的β细胞靶向分子的整合。这是该应用的目的是：1。与化学接头的TGF-β抑制剂合成，以补充我们的新型DYRK1A抑制剂接头化合物，以与针对原型的靶向输送车结合。 2。将Harmine链链链和TGF-beta抑制剂结合物结合到两个靶向分子的原型：GLP1受体激动剂和ENTPD3单克隆抗体。 3。在人类胰岛植入模型中，体内的Harmine-Linker和TGF-beta抑制剂结合物的长期疗效，特异性和安全性的定义。这些目标既成功，又直接响应了NIDDK目标的目标。如果GLP1受体激动剂和/或ENTPD3 mAb证明了β细胞靶向的次优，此处开发的方法和分子很容易被扩展并适应任何更特定的人类β细胞靶向分子。