Translation of Novel Therapeutic Targets in Multiple Myeloma

多发性骨髓瘤新治疗靶点的转化

基本信息

批准号：
9191248
负责人：
ALEXANDER KEITH STEWART
金额：
$ 43.19万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-22 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9191248
关键词：
Attention Bortezomib Brain Cancer Therapy Evaluation Program Cell Line Cells Characteristics Chemical Structure Chemicals Chronic Clinic Clinical Clinical Trials Combined Modality Therapy Cyclin-Dependent Kinase 5 Cyclin-Dependent Kinase Inhibitor Exhibits Formulation Fostering GPR6 gene GRK6 gene Genomics Goals In Vitro Knockout Mice Lead Libraries Malignant Neoplasms Mediator of activation protein Modeling Molecular Molecular Analysis Molecular Probes Multiple Myeloma Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Phosphotransferases Process Proteasome Inhibition Proteasome Inhibitor RNA Interference RNA interference screen Refractory Regimen Relapse Research Resistance Sampling Series Specificity Structure-Activity Relationship TFE3 gene TNK1 gene TOP1 gene Therapeutic Index Tissues Toxic effect Transgenic Organisms Translations Validation Work base clinical development clinical efficacy cytotoxicity disorder control genome-wide improved in vivo inhibitor/antagonist innovation kinase inhibitor lenalidomide nanomolar new therapeutic target novel preclinical study public health relevance research clinical testing scaffold screening small molecule inhibitor small molecule libraries synergism tumor

项目摘要

DESCRIPTION (provided by applicant): This application will build on genome wide RNA interference (RNAi) screens which successfully identified unique druggable targets in Myeloma. These targets were pursued into the clinic and remarkably have confirmed a new and active kinase inhibitor previously unrecognized as critical to Myeloma survival; cyclin dependent kinase 5 (CDK5). The screen also identified novel opportunities to target a second new, and hematologic tissue restricted, kinase target: G protein coupled receptor 6 (GRK6). We therefore present an ambitious short and midterm plan to further clinically develop and understand the molecular basis for the activity of the CDK5 inhibitor, SCH727965, while taking a longer term view by pursuing novel chemical entities targeting GRK6. The aims of the proposal are to: 1) Further advance CDK5 suppressive therapy in the clinic by conducting a Phase Ib/II clinical trial of SCH727965 in combination with the proteasome inhibitor Carfilzomib in advanced Myeloma, 2) As part of this clinical trial we will examine in vivo mediators of sensitivity and resistance t the combination therapy, 3) Using molecular probe chemicals generated from a 120,000 compound, scaffold enriched, library screen we will examine a panel of 40 novel GRK6 specific inhibitors for target specificity, potency, in vivo activity and toxicity against Myeloma. Lead compounds will be assessed for toxicity profile as a prelude to lead optimization and early clinical development, 4) we will continue analysis of targets identified in BTZ sensitizing screens that have not yet been fully validated. We have focused early attention on GRK6 and CDK5 as the strongest hits with the highest apparent therapeutic index but other novel and interesting proteasome inhibitor sensitizing targets identified in our RNA interference screens require further validation and analysis and include the sensitizers BAZ1B, CDC42SE2, MDM4, NME7, RAB8B, TFE3, TNFAIP3, TNK1, TOP1, VAMP2, and YY1. The proposed work is therefore highly innovative, pursuing at least two new and novel targets to clinical conclusion and is of high significance as further breakthroughs in therapy and new therapeutic targets for Myeloma are needed to turn the disease from controllable to curable.

描述（由申请人提供）：此应用将建立在基因组宽RNA干扰（RNAi）筛选的基础上，该筛查成功地鉴定了骨髓瘤中的独特可药物靶标。这些靶标被追捕到诊所中，并明显地证实了一种先前未被认为对骨髓瘤生存至关重要的新型活性激酶抑制剂。细胞周期蛋白依赖性激酶5（CDK5）。屏幕还确定了靶向第二个新的和血液组织限制的激酶靶标：G蛋白偶联受体6（GRK6）的新机会。因此，我们提出了一个雄心勃勃的短期和中期计划，以进一步在临床上发展和理解CDK5抑制剂SCH727965活性的分子基础，同时通过追求针对GRK6的新型化学实体来进行长期视野。 The aims of the proposal are to: 1) Further advance CDK5 suppressive therapy in the clinic by conducting a Phase Ib/II clinical trial of SCH727965 in combination with the proteasome inhibitor Carfilzomib in advanced Myeloma, 2) As part of this clinical trial we will examine in vivo mediators of sensitivity and resistance t the combination therapy, 3) Using molecular probe chemicals generated from a 120,000化合物，脚手架富集，图书馆屏幕我们将检查一个40个新型GRK6特异性抑制剂的小组，以实现目标特异性，效力，体内活性和对骨髓瘤的毒性。将评估铅化合物的毒性特征，作为铅优化和早期临床开发的前奏，4）我们将继续分析BTZ敏感筛选中确定的靶标尚未得到充分验证。 We have focused early attention on GRK6 and CDK5 as the strongest hits with the highest apparent therapeutic index but other novel and interesting proteasome inhibitor sensitizing targets identified in our RNA interference screens require further validation and analysis and include the sensitizers BAZ1B, CDC42SE2, MDM4, NME7, RAB8B, TFE3, TNFAIP3, TNK1, TOP1, VAMP2和YY1。因此，拟议的工作具有高度创新性，至少追求两个新的和新的靶标，以实现临床结论，并且具有很高的意义，因为需要进一步的治疗突破，需要对骨髓瘤的新治疗靶标才能将疾病从可控制的治疗转变为可治愈。