CDK8/19 inhibitors for therapy of advanced prostate cancer

CDK8/19抑制剂用于治疗晚期前列腺癌

基本信息

批准号：
10163807
负责人：
Mengqian Chen
金额：
$ 84.63万
依托单位：
SENEX BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-23 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163807
关键词：
Aftercare Androgen Receptor Androgens Animal Model Antiandrogen Therapy Biological Availability Biotechnology Castration Cell Line Characteristics Chemicals Clinic Clinical Clinical Research Clinical Trials Clinical Trials Design Collaborations Cytotoxic agent Development Disease Drug Kinetics Enzymes Excipients Formulation Gene Expression Genes Genetic Transcription Genomics Goals Growth Lead Malignant Neoplasms Malignant neoplasm of prostate Medical Molecular Monkeys Mus Neoplasm Metastasis Pathway interactions Patient Selection Patients Pharmaceutical Preparations Phase Phosphotransferases Play Process Production Prostate Prostate Cancer therapy RNA Splicing Refractory Resistance Series Site Small Business Innovation Research Grant Solvents South Carolina Stromal Cells Testing Toxic effect Treatment Failure Twin Multiple Birth Universities Variant Vertebral column Xenograft Model abiraterone advanced prostate cancer androgen deprivation therapy androgen independent prostate cancer base bone cancer drug resistance combinatorial deprivation drug candidate forest implantation in vivo in vivo Model inhibitor/antagonist liquid formulation medical schools men molecular marker novel drug class patient derived xenograft model preclinical development preclinical study prevent programs prostate cancer cell line prostate cancer model response transcriptional reprogramming transcriptomics tumor tumor growth tumor xenograft

项目摘要

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.

大多数前列腺癌的生长是由雄激素受体（AR）驱动的，这是一种转录调节剂促进肿瘤和肿瘤抑制活性。侵略性前列腺癌通过雄激素治疗剥夺疗法，但有时会发展为castration-fractration-Fractory Prostate Cancer（CRPC），目前是无法治愈。随着CRPC的变化与雄激素无关的，通常是由于组成性活性AR变体的表达，尤其是AR-V7。新AR 发育中的拮抗剂导致AR及其与雄激素无关的变体的降解，但AR具有不仅是肿瘤促进的，而且是肿瘤抑制活性，将被这种药物消除。因此，迫切需要对不依赖雄激素的CRPC有效的新型药物。为了实现这一目标，我们针对“双”激酶CDK8和CDK19，它们调节转录重编程，抗癌耐药性和转移所需的关键过程。 CDK8和CDK19 临床前列腺癌中的表达与CRPC和治疗失败密切相关。塞内克斯生物技术已经开发了第一个选择性CDK8/19抑制剂。最近确定的铅化合物显示出极好的体内效力和药代动力学。 CDK8/19抑制剂对长时间给药并显示了不同癌症的有益活动，包括对转移性肿瘤。 CDK8/19抑制剂，与抗雄激素治疗结合使用，抑制CRPC的生长体内，在AR-V7表达CRPC模型中观察到了强大的效果。组合效应 CDK8/19抑制和抗雄激素治疗与肿瘤中基因表达的变化有关并在基质中。拟议的II期SBIR计划的目标是确定分子特征使它们容易受到CDK8/19抑制作用的CRPC，以确定CDK8/19抑制剂是否有效 CRPC在转移部位生长，并优化铅CDK8/19抑制剂的公式。实现这些目标，我们将筛选一个基于细胞线的和患者衍生的用于体内的Xenographic CRPC模型对CDK8/19抑制作用的反应结合了castration或enzalutamide。观察到的回答将是与治疗前后的肿瘤基因组学和基因表达相关，以鉴定分子对CDK8/19抑制剂的敏感性结合抗雄激素治疗的决定因素。我们还将评估铅CDK8/19抑制剂对原位植入后CRPC生长和转移性扩散的影响关于骨骼的CRPC生长，骨骼是诊所的主要转移部位。同时，我们将优化铅CDK8/19抑制剂候选者的形成，以获得最佳的药代动力学。完成后该计划，CDK8/19抑制剂候选药物将准备好进行研究，并生成信息将用于指导患者的选择和临床试验的设计。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins.

DOI：
10.1093/nar/gkad538
发表时间：
2023-08-11
期刊：
Nucleic acids research
影响因子：
14.9
作者：
通讯作者：

A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics.

DOI：
10.1021/acs.jmedchem.1c01951
发表时间：
2022-02
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Li Zhang;Chen Cheng;Jing Li;Lili Wang;A. Chumanevich;Donald C. Porter;Aleksei Mindich;S. Gorbunova;I. Roninson;Mengqian Chen;Campbell McInnes
通讯作者：
Li Zhang;Chen Cheng;Jing Li;Lili Wang;A. Chumanevich;Donald C. Porter;Aleksei Mindich;S. Gorbunova;I. Roninson;Mengqian Chen;Campbell McInnes

Inhibition of CDK8/19 Mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo.