Project 1: Targeting the MYC Pathway in Prostate Cancer

项目 1：靶向前列腺癌中的 MYC 通路

• 批准号: 10089063
• 负责人: Sarki A. Abdulkadir
• 金额: $ 36.4万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-18 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10089063
• 关键词: Address; Animal Model; Antiandrogen Therapy; Apoptosis; Binding; Biological Assay; CWR22Rv1; Castration; Cells; Chromatin; Clinical; Complex; Coupled; Data; Disease; Drug Kinetics; Gene Amplification; Gene Expression; Genetic Transcription; Goals; Heterodimerization; Human; Impairment; In Vitro; Lead; Link; MYC Family Protein; Malignant Neoplasms; Malignant neoplasm of prostate; Maximum Tolerated Dose; Mediating; Modeling; Mus; Neuroendocrine Prostate Cancer; Oncogenes; Oncoproteins; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphorylation; Play; Pre-Clinical Model; Prostate Cancer therapy; RNA Splicing; Recurrence; Regulation; Resistance; Role; Safety; Series; Specificity; Therapeutic; Threonine; Toxicology; Tumor Tissue; Tumorigenicity; Ubiquitin; Up-Regulation; base; c-myc Genes; castration resistant prostate cancer; chemical genetics; circulating DNA; clinical application; cohort; cytotoxicity; genetic approach; in silico; in vivo; in vivo Model; inhibitor/antagonist; leukemia; meetings; mouse model; multicatalytic endopeptidase complex; novel; novel therapeutics; overexpression; pharmacodynamic biomarker; pharmacophore; phase I trial; pre-clinical; preclinical study; prostate cancer cell; prostate cancer cell line; prostate cancer model; protein expression; research clinical testing; scaffold; small molecule; small molecule inhibitor; small molecule libraries; therapy resistant; tumor; tumor growth; Address; Animal Model; Antiandrogen Therapy; Apoptosis; Binding; Biological Assay; CWR22Rv1; Castration; Cells; Chromatin; Clinical; Complex; Coupled; Data; Disease; Drug Kinetics; Gene Amplification; Gene Expression; Genetic Transcription; Goals; Heterodimerization; Human; Impairment; In Vitro; Lead; Link; MYC Family Protein; Malignant Neoplasms; Malignant neoplasm of prostate; Maximum Tolerated Dose; Mediating; Modeling; Mus; Neuroendocrine Prostate Cancer; Oncogenes; Oncoproteins; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphorylation; Play; Pre-Clinical Model; Prostate Cancer therapy; RNA Splicing; Recurrence; Regulation; Resistance; Role; Safety; Series; Specificity; Therapeutic; Threonine; Toxicology; Tumor Tissue; Tumorigenicity; Ubiquitin; Up-Regulation; base; c-myc Genes; castration resistant prostate cancer; chemical genetics; circulating DNA; clinical application; cohort; cytotoxicity; genetic approach; in silico; in vivo; in vivo Model; inhibitor/antagonist; leukemia; meetings; mouse model; multicatalytic endopeptidase complex; novel; novel therapeutics; overexpression; pharmacodynamic biomarker; pharmacophore; phase I trial; pre-clinical; preclinical study; prostate cancer cell; prostate cancer cell line; prostate cancer model; protein expression; research clinical testing; scaffold; small molecule; small molecule inhibitor; small molecule libraries; therapy resistant; tumor; tumor growth

PROJECT 1: ABSTRACT MYC oncoproteins (including c-MYC, L-MYC and N-MYC) have been implicated in up to 70% of all human cancers. In prostate cancer, elevated levels of MYC protein expression are observed across all grades. In castration-resistant prostate cancer (CRPC), there is evidence of further upregulation of c-MYC levels with gene amplification occurring in 45% of cases. In late-stage, therapy-resistant neuroendocrine prostate cancer (NEPC), N-MYC is overexpressed in 40% of cases. In preclinical studies, inhibition of MYC can effectively kill CRPC and NEPC cells. A viable therapeutic strategy to inhibit MYC is therefore likely to have a significant impact on this disease and to fulfill the ongoing need for novel impactful therapies spanning the spectrum of castration resistant prostate cancer. Despite its recognition as an attractive cancer target, MYC has proved difficult to target, and there are currently no clinically viable small molecule MYC inhibitors (MYCi) available. By employing a pharmacophore-based in silico screen of a large chemical library (32 million compounds) coupled to a rapid in vivo screen in mice, we identified a series of novel small molecule inhibitors. These MYC inhibitors are highly drug-like and have shown excellent pharmacokinetic, toxicological and anti-tumor activity profiles in MYC-driven models of prostate cancer and leukemia. The compounds engage MYC inside cells as shown by the cellular thermal shift assay (CETSA); disrupt MYC/MAX complex formation which is required for MYC activity; and inhibit MYC-driven target gene expression. Furthermore, the MYCi compounds enhance phosphorylation of MYC on threonine-58 (T58P) which promotes MYC degradation via a well-characterized ubiquitin-proteasome pathway. Consequently, treatment with MYCi impaired tumorigenicity in vitro and in vivo. The goals of this project are to develop the lead MYC inhibitor, MYCi975, for clinical application in the treatment of prostate cancer and to characterize the mechanisms of MYCi-induced degradation of c-MYC and N-MYC oncoproteins. We will implement the following Specific Aims: Aim 1 is to investigate the mechanisms of MYCi975 regulation of c- MYC and N-MYC phosphorylation and stability and the potential of MYC pT58 as a pharmacodynamic marker. Aim 2 will assess MYCi anti-tumor efficacy and impact on pharmacodynamic biomarkers in preclinical models of c-MYC and N-MYC driven prostate cancer. Aim 3 will seek to develop MYCi975 for use in patients by conducting formal IND-enabling toxicology studies and initiate a phase 1 trial in mCRPC patients. Impact: Successful completion of these studies could lead to first-in-class therapies for lethal prostate cancers dependent on c-MYC/N-MYC activity. This benefit can extend to other human cancers as well because of the pervasive role MYC proteins play in cancers of all types.

项目1：摘要 MYC癌蛋白（包括C-MYC，L-MYC和N-MYC）已涉及多达70％的人类 癌症。在前列腺癌中，所有等级均观察到MYC蛋白表达的水平升高。在 costatration抗性前列腺癌（CRPC），有证据表明C-MYC水平进一步上调了基因 45％的病例发生放大。在后期，耐治疗的神经内分泌前列腺癌（NEPC）， N-MYC在40％的病例中过表达。在临床前研究中，抑制MYC可以有效地杀死CRPC和 NEPC细胞。因此，可行的抑制MYC的可行治疗策略可能对此产生重大影响 疾病并满足持续的持续影响跨越cast割的新型有影响力疗法的需求 前列腺癌。尽管MYC被认为是有吸引力的癌症靶标，但事实证明很难靶向。 目前尚无临床上可行的小分子MYC抑制剂（MYCI）。通过使用 在大型化学库（3200万种化合物）的硅屏幕中基于药效团 在小鼠中，我们确定了一系列新型的小分子抑制剂。这些MYC抑制剂高度高 类似药物，并且在MYC驱动的 前列腺癌和白血病的模型。这些化合物接合MYC内部细胞内部，如细胞所示 热移测定法（CETSA）； MYC活动所需的MYC/MAX复杂形成；并抑制 MYC驱动的靶基因表达。此外，Myci化合物增强了MYC的磷酸化 苏氨酸-58（T58P）通过特征良好的泛素 - 蛋白酶体途径促进MYC降解。 因此，用myci治疗在体外和体内损害了肿瘤性。该项目的目标是 开发铅MYC抑制剂MyCI975，用于治疗前列腺癌和 表征Myci诱导的C-MYC和N-MYC癌蛋白降解的机制。我们将 实施以下具体目的：目标1是研究myci975 c-调节的机制 MYC和N-MYC磷酸化和稳定性以及MYC PT58作为药效标记的潜力。 AIM 2将评估临床前模型中的Myci抗肿瘤功效和对药效生物标志物的影响 C-MYC和N-MYC驱动的前列腺癌。 AIM 3将寻求开发Myci975，以在患者中使用 在MCRPC患者中进行正式的毒理学研究并启动1期试验。 影响：这些研究的成功完成可能会导致对致命前列腺癌的第一类疗法 取决于C-MYC/N-MYC活性。由于 普遍的角色MYC蛋白在所有类型的癌症中起着。