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

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）与高达 70% 的人类癌蛋白有关 癌症。在前列腺癌中，所有级别的 MYC 蛋白表达水平均升高。在 去势抵抗性前列腺癌 (CRPC)，有证据表明基因进一步上调 c-MYC 水平 45% 的病例发生扩增。在晚期、难治性神经内分泌前列腺癌 (NEPC) 中， N-MYC 在 40% 的病例中过度表达。在临床前研究中，抑制MYC可以有效杀灭CRPC和 NEPC 细胞。因此，抑制 MYC 的可行治疗策略可能会对此产生重大影响。 疾病并满足对跨越去势抵抗谱系的新型有效疗法的持续需求 前列腺癌。尽管 MYC 被认为是一个有吸引力的癌症靶点，但事实证明它很难靶向，并且 目前尚无临床上可行的小分子 MYC 抑制剂 (MYCi)。通过雇用 基于药效团的大型化学库（3200 万种化合物）的计算机筛选，并结合快速分析 通过小鼠体内筛选，我们鉴定出一系列新型小分子抑制剂。这些 MYC 抑制剂具有高度 类似药物，并在 MYC 驱动中表现出优异的药代动力学、毒理学和抗肿瘤活性特征 前列腺癌和白血病模型。这些化合物与细胞内的 MYC 结合，如细胞 热位移测定（CETSA）；破坏 MYC 活性所需的 MYC/MAX 复合物形成；并抑制 MYC 驱动的靶基因表达。此外，MYCi 化合物增强 MYC 的磷酸化 苏氨酸-58 (T58P)，通过充分表征的泛素蛋白酶体途径促进 MYC 降解。 因此，MYCi 治疗会损害体外和体内的致瘤性。该项目的目标是 开发领先的 MYC 抑制剂 MYCi975，用于临床治疗前列腺癌并 描述 MYCi 诱导 c-MYC 和 N-MYC 癌蛋白降解的机制。我们将 实现以下具体目标： 目标 1 是研究 MYCi975 调节 c-的机制 MYC 和 N-MYC 磷酸化和稳定性以及 MYC pT58 作为药效标记物的潜力。 目标 2 将评估 MYCi 的抗肿瘤功效以及对临床前模型中药效生物标志物的影响 c-MYC 和 N-MYC 驱动的前列腺癌。目标 3 将寻求开发 MYCi975 用于患者 开展正式的 IND 毒理学研究，并在 mCRPC 患者中启动 1 期试验。 影响：成功完成这些研究可能会带来针对致命性前列腺癌的一流疗法 依赖于 c-MYC/N-MYC 活性。这种益处也可以扩展到其他人类癌症，因为 MYC 蛋白在所有类型的癌症中发挥着普遍作用。