Translation of Novel Therapeutic Targets in Multiple Myeloma

描述（由申请人提供）：本申请将建立在全基因组RNA干扰（RNAi）筛选的基础上，该筛选成功鉴定了骨髓瘤中独特的可药用靶点。这些目标被追求到临床上，并显着证实了一种新的和活性激酶抑制剂，以前未被识别为骨髓瘤生存的关键;细胞周期蛋白依赖性激酶5（CDK 5）。筛选还确定了靶向第二个新的血液组织限制性激酶靶点的新机会：G蛋白偶联受体6（GRK 6）。因此，我们提出了一个雄心勃勃的短期和中期计划，以进一步临床开发和理解CDK 5抑制剂SCH 727965活性的分子基础，同时通过追求靶向GRK 6的新型化学实体来实现更长远的目标。该提案的目的是：1）通过在晚期骨髓瘤中进行SCH 727965与蛋白酶体抑制剂Carfilzelatin组合的Ib/II期临床试验，进一步推进临床中的CDK 5抑制疗法，2）作为该临床试验的一部分，我们将检查组合疗法的敏感性和抗性的体内介质，3）使用从120，我们将检查一组40种新型GRK 6特异性抑制剂的靶特异性、效力、体内活性和针对骨髓瘤的毒性。作为先导化合物优化和早期临床开发的前奏，将评估先导化合物的毒性特征，4）我们将继续分析BTZ致敏筛选中确定的靶点 尚未完全验证。我们早期关注GRK 6和CDK 5作为具有最高表观治疗指数的最强命中，但在我们的RNA干扰筛选中鉴定的其他新颖且有趣的蛋白酶体抑制剂敏化靶点需要进一步验证和分析，包括敏化剂BAZ 1B、CDC 42 SE 2、MDM 4、NME 7、RAB 8B、TFE 3、TNFAIP 3、TNK 1、TOP 1、VAMP 2和YY 1。因此，所提出的工作具有高度创新性，追求至少两个新的和新颖的靶点以获得临床结论，并且具有重要意义，因为需要骨髓瘤治疗的进一步突破和新的治疗靶点来将疾病从可控变为可治愈。

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.