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

基本信息

批准号：
10165036
负责人：
DONALD DURDEN
金额：
$ 48.71万
依托单位：
CAROLINAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-27 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165036
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

项目摘要

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.

抑制关键的癌症转录促进因子 MYC（c-MYC 和 MYCN）的需求尚未得到满足作用于许多细胞受体和信号转录途径的下游，以激活癌细胞的基因迄今为止，MYC 的小分子抑制剂。在我们的初步数据中，我们开发了一种先导化合物 SF2523，它显示出有效的作用。通过阻断 PI-3 激酶 (PI-3K) 和高度显性调节因子对 MYC 产生正交抑制活性表观遗传机制 BRD4 在此，我们着手通过额外的方法开发 SF2523 和其他化学型。硅晶体结构和核磁共振分析和优化，为高级临床前研究做准备 Myc 依赖性癌症的治疗应用。转录因子 MYC（c-MYC 和 MYCN）在癌症生长、增殖、存活、最近在抗肿瘤免疫的控制中，它在大多数人类的亚群中过度表达。导致对 PI-3K 和其他信号通路抑制剂产生耐药性的癌症 MYC 和 PI-3K 都很好。已确定的癌蛋白被证实是许多肿瘤类型的驱动因素。迅速成为转录组和癌细胞抗性的主要表观遗传调节因子因此，癌症生物学领域普遍认为抑制 BRD4。和/或 MYC 应证明对多种癌症有益，其中 MYC 是肿瘤细胞的既定调节剂我们的创新方法以我们的中心假设为中心，即双重 PI- 3K/BRD4 抑制剂 SF2523 将通过 PI-3K 抑制增强 MYC 的降解，从而有效抑制 MYC 活性 AND 通过 BRD4 抑制来阻断 MYC 转录活性我们的初步数据支持我们在这方面的成功。我们解析了BRD4活性位点SF2523的晶体结构并测定了结构活性通过经过验证的分子模型研究设计的围绕双 PI-3K/BRD4 抑制剂的关系 (SAR) 证明了我们的双靶向单一抑制剂的安全性与使用两种抑制剂的累积毒性的比较我们的初步研究支持我们的具体目标，其中包括：1）SAR 优化围绕我们的晶体结构和 NMR 分析（目标 2）构建的双重抑制化学型（目标 1）与 2）评估每种口服优化化学型的安全性、PK/PD模型和抗肿瘤功效（目标3）。我们提案的目标是推进这种新型双 PI 的临床前开发和验证 3K/BRD4 抑制剂 SF2523 或其衍生物作为对抗 PI-3K/MYC 驱动的恶性肿瘤的最终候选药物死亡率高，例如肝细胞癌 (HCC) 和头颈部鳞状细胞癌（SCCHN）并获得最终开发的优化口头候选者。此外，我们的目标是确定。当我们迈向 I 期临床时，PI-3K 和 MYC 肿瘤特征将定义对 SF2523 的敏感性这种“同类首创”双重 PI-3K/BRD4 抑制化学型用于个体化癌症治疗的试验。