Translation of Novel Therapeutic Targets in Multiple Myeloma

描述（由申请人提供）：该申请将建立在全基因组RNA干扰（RNAi）筛选的基础上，该筛选成功地鉴定了骨髓瘤中独特的可药物靶点。这些靶点已进入临床，并显著证实了一种新的活性激酶抑制剂，以前未被认识到对骨髓瘤生存至关重要；细胞周期蛋白依赖性激酶5 （CDK5）。筛选还发现了针对第二个新的血液学组织受限激酶靶点的新机会：G蛋白偶联受体6 （GRK6）。因此，我们提出了一项雄心勃勃的短期和中期计划，以进一步临床开发和了解CDK5抑制剂SCH727965活性的分子基础，同时通过寻求针对GRK6的新型化学实体来采取长期观点。该建议的目的是：1)通过开展SCH727965联合蛋白酶体抑制剂卡非佐米治疗晚期骨髓瘤的Ib/II期临床试验，进一步推进CDK5抑制治疗；2)作为该临床试验的一部分，我们将检查体内介质对联合治疗的敏感性和耐药性；3)使用由120,000化合物生成的分子探针化学物质，支架丰富，文库筛选我们将检查一组40种新的GRK6特异性抑制剂的靶特异性、效力、体内活性和对骨髓瘤的毒性。先导化合物的毒性评估将作为先导优化和早期临床开发的前奏。4)我们将继续分析BTZ致敏筛选中确定的靶点

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.