CDK8/19 inhibitors for therapy of advanced prostate cancer

大多数前列腺癌的生长是由雄激素受体（AR）驱动的，AR是一种转录调节因子， 肿瘤促进和肿瘤抑制活性。侵袭性前列腺癌通过雄激素治疗 剥夺治疗，但最终进展为去势难治性前列腺癌（CRPC），目前 无法治愈有效的AR拮抗剂和抑制雄激素产生的药物最终会失败，因为CRPC会成为 雄激素非依赖性，通常是由于组成型活性AR变体，特别是AR-V7的表达。新的ar 开发中的拮抗剂引起AR及其雄激素非依赖性变体的降解， 不仅具有肿瘤促进活性，而且具有肿瘤抑制活性，这些活性将被这些药物消除。因此，我们认为， 迫切需要有效对抗雄激素非依赖性CRPC的新型药物。 为了实现这一目标，我们靶向"孪生"激酶CDK8和CDK19，它们调节转录水平。 重编程是癌症耐药性和转移所需的关键过程。cdk8和cdk19 在临床前列腺癌中的表达与CRPC和治疗失败密切相关。森纳士 生物技术已经开发出第一种选择性CDK8/19抑制剂;最近发现的先导化合物 显示出优异的体内效力和药代动力学。CDK8/19抑制剂在施用后不诱导明显的毒性。 延长给药时间并在不同癌症中显示出有益活性，包括抑制肿瘤细胞的生长 转移性肿瘤CDK8/19抑制剂与抗雄激素治疗联合使用时，可抑制CRPC生长， 在体内，在表达AR-V7的CRPC模型中观察到最强的作用。的组合作用 CDK8/19抑制和抗雄激素治疗与肿瘤中基因表达的变化相关， 和基质中。拟议的第二阶段SBIR计划的目标是确定分子特征， CRPC，使他们对CDK8/19抑制敏感，以确定CDK8/19抑制剂是否有效对抗 CRPC在转移部位生长，并优化主要CDK8/19抑制剂的配方。实现 为了实现这些目标，我们将筛选一组基于细胞系和患者来源的异种移植CRPC模型， 对CDK8/19抑制联合去势或恩杂鲁胺的反应。观察到的反应将是 与肿瘤基因组学及治疗前后基因表达相关， CDK8/19抑制剂联合抗雄激素治疗敏感性的决定因素。我们还将评估 CDK8/19先导抑制剂对CRPC原位植入后生长和转移扩散的影响， 对CRPC在骨中生长的影响，骨是临床上的主要转移部位。同时，我们将优化 在某些实施方案中，本发明的目的是提供一种先导CDK8/19抑制剂候选物的制剂，以实现最佳的药代动力学。完成后 在该计划中，CDK8/19抑制剂候选药物将准备用于IND使能研究， 这些信息将用于指导患者选择和临床试验设计。

The growth of most prostate cancers is driven by androgen receptor (AR), a transcriptional regulator that has both tumor-promoting and tumor-suppressive activities. Aggressive prostate cancer is treated through androgen deprivation therapy but eventually progresses to castration-refractory prostate cancer (CRPC), which is currently incurable. Potent AR antagonists and agents that inhibit androgen production eventually fail, as CRPC becomes androgen-independent, often due to the expression of constitutively active AR variants, notably AR-V7. New AR antagonists under development cause the degradation of AR and its androgen-independent variants but AR has not only a tumor-promoting but also a tumor-suppressive activity that will be abrogated by such drugs. Hence, novel classes of drugs that would be effective against androgen-independent CRPC are urgently needed. Towards this goal, we are targeting “twin” kinases CDK8 and CDK19, which regulate transcriptional reprogramming, a key process required for cancer drug resistance and metastasis. CDK8 and CDK19 expression in clinical prostate cancers is strongly associated with CRPC and treatment failure. Senex Biotechnology has developed the first selective CDK8/19 inhibitors; the most recently identified lead compound shows excellent in vivo potency and pharmacokinetics. CDK8/19 inhibitors induce no apparent toxicity upon prolonged administration and show beneficial activities in different cancers, including growth inhibition of metastatic tumors. CDK8/19 inhibitors, when combined with anti-androgen therapy, suppress CRPC growth in vivo, with the strongest effect observed in an AR-V7 expressing CRPC model. The combinatorial effect of CDK8/19 inhibition and anti-androgen therapy is associated with changes in gene expression both in the tumor and in the stroma. The goals of the proposed Phase II SBIR program are to identify molecular characteristics of CRPC that make them susceptible to CDK8/19 inhibition, to determine if CDK8/19 inhibitors are effective against CRPC growing at metastatic sites, and to optimize the formulation of the lead CDK8/19 inhibitor. To achieve these goals, we will screen a panel of cell-line based and patient-derived xenograft CRPC models for in vivo response to CDK8/19 inhibition combined with castration or enzalutamide. The observed responses will be correlated with the tumor genomics and gene expression before and after treatment, to identify molecular determinants of sensitivity to CDK8/19 inhibitor combined with anti-androgen therapy. We will also evaluate the effects of the lead CDK8/19 inhibitor on CRPC growth and metastatic spread after orthotopic implantation and on CRPC growth in the bone, the primary metastatic site in the clinic. Concurrently, we will optimize the formulation of the lead CDK8/19 inhibitor candidate to achieve the best pharmacokinetics. Upon completion of this program, the CDK8/19 inhibitor drug candidate will be ready for IND-enabling studies, and the generated information will be used to guide patient selection and the design of clinical trials.