Dual PI3K/BRD4 Inhibitory Chemotype for Maximum Inhibition of MYC and Cancer

双重 PI3K/BRD4 抑制化学型可最大程度地抑制 MYC 和癌症

• 批准号: 9828553
• 负责人: DONALD DURDEN
• 金额: --
• 依托单位: CAROLINAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-27 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9828553
• 关键词: 1-Phosphatidylinositol 3-Kinase; Academia; Active Sites; Adult; Alcohols; Automobile Driving; BAY 54-9085; Binding; Binding Sites; Bromodomain; CD47 gene; Cancer Biology; Catalytic Domain; Chemicals; Childhood; Childhood Solid Neoplasm; Clinical Trials; Collaborations; Combined Modality Therapy; Consensus; Crystallization; Data; Development; Diagnostic; Digit structure; Epigenetic Process; Evaluation; Formulation; Funding; Generations; Genetic Transcription; Goals; Grant; Growth; Head and Neck Squamous Cell Carcinoma; Human; Immunooncology; Industry; Laboratories; Lead; Legal patent; Lysine; MAP Kinase Gene; MYCN gene; Malignant Childhood Neoplasm; Malignant Epithelial Cell; Malignant Neoplasms; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Neuroblastoma; Oncogenes; Oncoproteins; Oral; PIK3CA gene; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Phosphotransferases; Play; Preparation; Primary carcinoma of the liver cells; Property; Proteins; Proto-Oncogene Proteins c-myc; Public Health; Receptor Cell; Receptor Signaling; Regulation; Reporting; Research; Resistance; Role; Safety; Signal Pathway; Specificity; Structural Models; Structure; Structure-Activity Relationship; Study models; Subgroup; Technology; Therapeutic; Therapeutic Studies; Toxic effect; Tumor Immunity; United States National Institutes of Health; Validation; Viral; adaptive immune response; analog; base; c-myc Genes; cancer cell; cancer therapy; cell transformation; clinical application; clinical candidate; clinical development; design; disability; drug candidate; immunoregulation; improved; in silico; in vitro testing; in vivo; inhibitor/antagonist; innovation; insight; medulloblastoma; molecular modeling; mortality; neoplastic cell; novel; novel therapeutics; overexpression; pharmacokinetics and pharmacodynamics; preclinical development; preclinical study; predictive marker; prognostic significance; programmed cell death ligand 1; scaffold; single molecule; small molecule; small molecule inhibitor; success; technology development; therapeutic evaluation; transcription factor; transcriptome; tumor; tumor growth; tumorigenesis; tumorigenic

There is an unmet need to inhibit the key cancer promoting transcription factor MYC (both c-MYC and MYCN) that act downstream of many cell receptors and signal transcription pathways to activate genes for cancer cell resistance, tumor growth and the control of antitumor immunity. To date, small molecule inhibitors of MYC have remained elusive. In our preliminary data, we developed a lead compound, SF2523 which displays potent orthogonal inhibitory activity against MYC by blocking PI-3 kinase (PI-3K) and the highly dominant regulator of epigenetic machinery, BRD4. Herein, we set out to develop SF2523 and other chemotypes through additional in silico crystal structure and NMR analysis and optimization in preparation for advanced preclinical studies for therapeutic application in Myc dependent cancers. The transcription factor, MYC (c-MYC and MYCN) plays a key role in cancer growth, proliferation, survival, and more recently in the control of antitumor immunity. It is overexpressed in a subgroup of most human cancers resulting in resistance to PI-3K and other signaling pathway inhibitors. Both MYC and PI-3K are well- established onco-proteins that are confirmed drivers in a large number of tumor types. Moreover, BRD4 is rapidly emerging as a dominant epigenetic regulator of the transcriptome and of cancer cell resistance to kinase inhibition. Therefore, there is general consensus in the cancer biology arena that inhibition of BRD4 and/or MYC should prove beneficial in multiple cancers where MYC is an established regulator of tumor cell transformation and resistance. Our innovative approach centers on our central hypothesis that a dual PI- 3K/BRD4 inhibitor, SF2523, will potently inhibit MYC activity by enhancing its degradation via PI-3K inhibition AND block MYC transcriptional activity via BRD4 inhibition. Our preliminary data supports our success in that we solved the crystal structure of SF2523 in the active site of BRD4 and determined the structure activity relationships (SAR) around dual PI-3K/BRD4 inhibitors designed by validated molecular modeling studies and demonstrated the safety of our dual-targeting single inhibitor versus the accumulated toxicity of using two separate inhibitors. Our preliminary studies support our specific aims which include: 1) SAR to optimize the dual inhibitory chemotype (Aim 1) built around our crystal structure and NMR analyses (Aim 2) in parallel with 2) the evaluation of safety, PK/PD modeling and antitumor efficacy of each oral optimized chemotype (Aim 3). The objective of our proposal is to advance the preclinical development and validation of this novel dual PI- 3K/BRD4 inhibitor, SF2523 or its derivative as a final drug candidate against PI-3K/MYC-driven malignancies with high mortality rates e.g. hepatocellular carcinoma (HCC) and squamous cell carcinoma of the head/neck (SCCHN) and obtain an optimized oral candidate for final development. Moreover, our aims seek to identify PI-3K and MYC tumor signatures which will define sensitivity to SF2523 as we move toward a Phase I clinical trial of this “first in class” dual PI-3K/BRD4 inhibitory chemotype for individualized cancer therapeutics.

毫无满足的需要抑制促进转录因子MYC的关键癌症（C-MYC和MYCN） 在许多细胞受体和信号转录途径的下游作用，以激活癌细胞的基因 阻力，肿瘤生长和抗肿瘤免疫的控制。迄今为止，MYC的小分子抑制剂 仍然难以捉摸。在我们的初步数据中，我们开发了一个铅化合物SF2523，它显示有效 通过阻断PI-3激酶（PI-3K）和高度主导的调节剂，对MYC的正交抑制活性 表观遗传机械，BRD4。本文中，我们着手通过额外的 在硅晶体结构以及NMR分析和优化中，为先进的临床前研究准备 MYC依赖性的治疗应用取消。 转录因子MYC（C-MYC和MYCN）在癌症生长，增殖，生存， 最近，用于控制抗肿瘤免疫力。它在大多数人的子组中过表达 导致对PI-3K和其他信号通路抑制剂的抗药性。 MYC和PI-3K都很好 已建立的Onco蛋白质是大量肿瘤类型的确认驱动因素。而且，BRD4是 迅速成为转录组和癌细胞抗性的主要表观遗传调节剂 激酶抑制。因此，在癌症生物学领域达成了一般共识，即抑制BRD4 和/或MYC应该在MYC是已建立的肿瘤细胞调节剂的多种癌症中证明有益 转化和阻力。我们的创新方法集中在我们的中心假设上，即双重假设 3K/BRD4抑制剂SF2523将通过PI-3K抑制来增强其降解，从而有可能抑制MYC活性 并通过BRD4抑制阻止MYC转录活性。我们的初步数据支持我们的成功 我们在BRD4的活性位点解决了SF2523的晶体结构，并确定了结构活性 通过经过验证的分子建模研究设计的双PI-3K/BRD4抑制剂的关系（SAR） 证明了我们双重目标的单个抑制剂的安全性，而不是使用两个抑制剂 单独的抑制剂。我们的初步研究支持我们的具体目标，其中包括：1）SAR优化 双重抑制性化学型（AIM 1）围绕我们的晶体结构和NMR分析（AIM 2）并行 2）评估每种口服优化化学型的安全性，PK/PD建模和抗肿瘤效率（AIM 3）。 我们提案的目的是推进这种新颖的双重旋转和验证 3K/BRD4抑制剂，SF2523或其衍生物作为针对PI-3K/MYC驱动的Malignancys的最终药物候选者 具有高死亡率，例如肝细胞癌（HCC）和头颈部的鳞状细胞癌 （SCCHN）并获得最终开发的优化口服候选者。而且，我们的目标试图确定 PI-3K和MYC肿瘤特征将在我们朝向I期临床的敏感性时定义对SF2523的敏感性 该“第一类”双PI-3K/BRD4抑制性化学型用于个性化癌症治疗的试验。