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 癌症。在前列腺癌中，在所有级别中都观察到MYC蛋白表达水平的升高。在……里面 抗去势前列腺癌(CRPC)，有证据表明c-myc基因水平进一步上调 45%的病例出现扩增。晚期，耐药神经内分泌前列腺癌(NEPC)， N-MYC在40%的病例中过度表达。在临床前研究中，抑制MYC可以有效地杀死CRPC和 NEPC细胞。因此，一种可行的抑制MYC的治疗策略可能会对此产生重大影响 以满足对跨越抗阉割的新的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目标，但事实证明，它很难成为目标，而且 目前尚无临床可行的小分子MYC抑制剂(MYCi)。通过雇用一名 基于药效团的电子筛选大型化学库(3200万种化合物)与快速进入 在小鼠体内筛选，我们发现了一系列新的小分子抑制剂。这些MYC抑制剂是高度 类药物，并在MYC驱动下显示出良好的药代动力学、毒理学和抗肿瘤活性 前列腺癌和白血病的模型。这些化合物在细胞内与MYC结合，如细胞所示 热位移分析(CETSA)；干扰MYC活性所需的MYC/MAX复合体的形成；以及抑制 MYC驱动的靶基因表达。此外，MYCi化合物可促进MYC的磷酸化。 苏氨酸-58(T58P)，通过泛素-蛋白酶体途径促进MYC降解。 因此，MYCi的治疗在体外和体内都会损害肿瘤的致瘤性。该项目的目标是 开发先导MYC抑制剂MYCi975，用于前列腺癌的临床治疗和 研究MYCi诱导c-MYC和N-MYC癌蛋白降解的机制。我们会 实现以下具体目标：目标1研究MYCi975对c- MYC和N-MYC的磷酸化和稳定性以及MYC pT58作为药效学标志物的潜力。 AIM 2将在临床前模型中评估MYCi的抗肿瘤效果和对药效生物标志物的影响 C-MYC和N-MYC导致的前列腺癌。AIM 3将寻求开发MYCi975，供患者使用 进行正式的IND毒理学研究，并在mCRPC患者中启动1期试验。 影响：这些研究的成功完成可能导致致命前列腺癌的一流疗法 依赖于c-myc/N-myc活性。这一益处也可以延伸到其他人类癌症，因为 MYC蛋白在所有类型的癌症中都发挥着普遍的作用。