Project 1: Targeting the MYC Pathway in Prostate Cancer

项目1：摘要 MYC癌蛋白（包括c-MYC、L-MYC和N-MYC）与高达70%的人类肿瘤相关， 癌的在前列腺癌中，在所有等级中观察到MYC蛋白表达水平升高。在 在去势抵抗性前列腺癌（CRPC）中，有证据表明c-MYC水平随着基因的表达而进一步上调。 45%的病例发生扩增。在晚期、治疗抵抗性神经内分泌前列腺癌（NEPC）中， 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， NEPC细胞。因此，抑制MYC的可行治疗策略可能对此产生重大影响。 疾病，并满足对跨越去势抵抗谱的新型有效疗法的持续需求。 前列腺癌尽管它被认为是一个有吸引力的癌症靶点，但MYC已被证明难以靶向， 目前没有临床上可行的小分子MYC抑制剂（MYCi）可用。通过采用 基于药效团的大型化学库（3200万种化合物）的计算机筛选， 在小鼠体内筛选中，我们鉴定了一系列新的小分子抑制剂。这些MYC抑制剂高度 药物样，并已显示出良好的药代动力学，毒理学和抗肿瘤活性概况MYC驱动的 前列腺癌和白血病的模型。这些化合物与细胞内的MYC结合，如细胞内的MYC表达所示。 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（T58 P），其通过充分表征的泛素-蛋白酶体途径促进MYC降解。 因此，用MYCi处理损害体外和体内致瘤性。该项目的目标是 开发领先的MYC抑制剂MYCi 975，用于治疗前列腺癌的临床应用， 表征MYCi诱导的c-MYC和N-MYC癌蛋白降解的机制。我们将 实现以下具体目的：目的1是研究MYCi 975调节c- MYC和N-MYC磷酸化和稳定性以及MYC pT 58作为药效学标志物的潜力。 目标2将评估MYCi抗肿瘤疗效和对临床前模型中药效学生物标志物的影响 c-MYC和N-MYC导致的前列腺癌。目标3将寻求开发MYCi 975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：这些研究的成功完成可能会导致致命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的普遍作用。

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.