Translation of Novel Therapeutic Targets in Multiple Myeloma

描述(由申请人提供)：这项应用将建立在全基因组RNA干扰(RNAi)筛查的基础上，成功地识别了骨髓瘤中独特的可用药靶点。这些靶点被用于临床，并显著地证实了一种新的、活性的激酶抑制剂，以前没有被认为是骨髓瘤生存的关键，即细胞周期蛋白依赖性激酶5(CDK5)。该筛查还确定了靶向第二个新的、血液组织受限的激酶靶点的新机会：G蛋白偶联受体6(GRK6)。因此，我们提出了一个雄心勃勃的中短期计划，以进一步在临床上开发和了解CDK5抑制剂SCH727965的活性的分子基础，同时通过寻找针对GRK6的新的化学实体来着眼于更长远的观点。该建议的目的是：1)通过开展SCH727965与蛋白酶体抑制剂Carfilzomib联合治疗晚期骨髓瘤的Ib/II期临床试验，进一步推动CDK5抑制治疗在临床上的应用；2)作为这项临床试验的一部分，我们将在体内检测联合治疗的敏感性和耐药性的介体；3)使用从120,000种化合物产生的分子探针化学物质，进行支架浓缩、文库筛选，以检测一组40种新型GRK6特异性抑制剂的靶向特异性、效力、体内活性和抗骨髓瘤毒性。将评估先导化合物的毒性，作为先导优化和早期临床开发的前奏，4)我们将继续分析在BTZ增敏筛查中确定的目标 还没有得到充分的验证。我们将早期的注意力集中在GRK6和CDK5上，认为它们是最强的靶点，具有最高的明显治疗指数，但在我们的RNA干扰筛选中发现的其他新的和有趣的蛋白酶体抑制敏化靶点需要进一步的验证和分析，包括增敏剂BAZ1B、CDC42SE2、MDM4、NME7、RAB8B、TFE3、TNFAIP3、TNK1、TOP1、VAMP2和Y1。因此，这项拟议的工作具有很高的创新性，至少追求两个新的临床靶点，具有重要意义，因为需要在治疗方面取得进一步突破，并建立新的治疗靶点，将骨髓瘤从可控转变为可治愈。

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.