Maximal MYC control using dual PI-3K/BRD4 (kinase/epigenetic) inhibitors

使用双 PI-3K/BRD4（激酶/表观遗传）抑制剂最大程度地控制 MYC

• 批准号: 8834750
• 负责人: DONALD DURDEN
• 金额: $ 20.9万
• 依托单位: SIGNALRX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834750
• 关键词: 1-Phosphatidylinositol 3-Kinase; Academia; Adult; Area; Back; Binding; Binding Sites; Biological Assay; Bromodomain; Cancer Cell Growth; Cancer Patient; Cancer cell line; Catalytic Domain; Cell Line; Cell Proliferation; Childhood; Childhood Solid Neoplasm; Chromatin; Chromones; Clinic; Clinical; Clinical Trials; Collaborations; Complex; Computer Simulation; Data; Data Set; Development; Docking; Drug Combinations; Epigenetic Process; Evaluation; FDA approved; Genes; Genetic Transcription; Goals; Growth; Human; In Vitro; Individual; Industry; Inhibitory Concentration 50; Knowledge; Laboratories; Lead; Literature; Lysine; MYC gene; MYCN gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Mission; Mitotic Cell Cycle; Modeling; Molecular; Molecular Models; Morbidity - disease rate; Mus; Neoplasm Metastasis; Neuroblastoma; Neurons; Nodal; Normal Cell; Outcome; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Process; Property; Proteins; Proto-Oncogene Proteins c-myc; Proto-Oncogenes; Public Health; Receptor Cell; Reporting; Research; Resistance; Signal Transduction; Signal Transduction Pathway; Staging; Structure-Activity Relationship; Therapeutic; Therapeutic Agents; Therapeutic Index; Toxic effect; Vertebral column; Work; angiogenesis; anticancer activity; anticancer research; base; c-myc Genes; cancer cell; cancer stem cell; cancer therapy; common treatment; cost; design; disability; improved; inhibitor/antagonist; innovation; kinase inhibitor; knowledge base; medulloblastoma; molecular modeling; mortality; mouse model; nerve stem cell; novel; novel therapeutics; public health relevance; research clinical testing; scaffold; single molecule; small molecule; targeted treatment; technology development; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): There is an unmet need to inhibit the key cancer promoting transcription factor MYC. MYC (both cMYC and MYCN) acts downstream of many cell receptor complexes and signal transduction pathways to activate genes that drive cancer cell growth and proliferation. To date, small molecule inhibitors of MYC have been elusive. An innovative approach would be to indirectly orthogonally diminish the activity of MYC by enhancing its degradation using PI-3 kinase (PI-3K) inhibitors combined with blocking transcription of the gene producing MYC using inhibitors of the bromodomain protein BRD4. While small molecule inhibitors or PI-3K and BRD4 are individually used in cancer clinical trials, none has made it through development to FDA approval. Although combination treatments are common in cancer, there is an unmet need for every increasing combinations to inhibit multiple targets to maximize efficacy. This becomes unfeasible due to prohibitive costs when combining expensive targeted therapies in addition to being a barrier to early clinical evaluation of such complex combinations of drugs. While exploring a novel PI-3K inhibitor scaffold, thienopyranone (TP) scaffold based on a chromone derivative we discovered that these compounds also can potently inhibit BRD4 (preliminary results). The chromone backbone is common to the inhibition of BOTH targets thus providing the opportunity to now explore the newly found BRD4 activity while maintaining potent PI-3K activity (overall objective). Consolidating the inhibition of PI-3K AND BRD4 to maximally inhibit MYC activity with one molecule would fill all the unmet needs stated above. This proposal will evaluate this approach by achieving the following aims setting the stage for phase II efforts to optimize the expected dual inhibitor lead compound(s) to a clinical candidate: Aim (Task) #1. Determine structure activity relationship (SAR) for TP compounds for BRD4 inhibition. Approach: Synthesize 30 TP compounds and determine their BRD4 and PI-3K inhibition profiles. Aim (Task) #2. Develop predictive computational BRD4 model for the in silico docking of designed compounds. Approach: Vary the molecular in silico fit parameters of the BRD4 model until docking predictions of a TP dataset correlates with actual BRD4 assay binding results creating a validated docking model. Aim (Task) #3. Determine effects on MYC and therapeutic index for dual BRD4/PI-3K inhibition. Approach: Determine MYC expression and activity levels and compare toxicity towards cancer cell lines versus normal cell lines when exposed to single BRD4 or PI-3K versus dual BRD4/PI-3K inhibition conditions. The contribution of this research is it provides an effective mechanism to block MYC activity that drives cancer and will be significant because it will allow enhanced combination treatments of MYC dependent cancers, such as CLL, medulloblastoma, and neuroblastoma. This approach is innovative because it attacks a key cancer target using two orthogonal mechanisms with a single compound and it challenges the cost-ignoring efficacy-limiting mentality of one-drug one-target prevalent in cancer research in an area with no FDA approved treatments.

描述（由申请人提供）：目前尚未满足抑制关键促癌转录因子MYC的需求。MYC（包括cMYC和MYCN）作用于许多细胞受体复合物和信号转导通路的下游，激活驱动癌细胞生长和增殖的基因。迄今为止，MYC的小分子抑制剂一直难以捉摸。一种创新的方法是通过使用PI-3激酶（PI-3K）抑制剂与使用溴结构域蛋白BRD4抑制剂阻断产生MYC的基因的转录来增强MYC的降解，从而间接地正交降低MYC的活性。虽然小分子抑制剂或PI-3K和BRD4单独用于癌症临床试验，但没有一种通过开发获得FDA批准。虽然联合治疗在癌症中很常见，但目前还不需要不断增加的联合治疗来抑制多个靶点以最大限度地提高疗效。这是不可行的，因为当结合昂贵的靶向治疗时，除了对这种复杂的药物组合进行早期临床评估的障碍之外，成本过高。在探索一种新的PI-3K抑制剂支架时，基于色素衍生物的噻吩吡喃酮（TP）支架我们发现这些化合物也可以有效抑制BRD4（初步结果）。这两种靶点的抑制都有共同的色素主干，因此提供了现在探索新发现的BRD4活性的机会，同时保持有效的PI-3K活性（总体目标）。巩固对PI-3K和BRD4的抑制，用一个分子最大限度地抑制MYC活性，将填补上述所有未满足的需求。本提案将通过实现以下目标来评估该方法，为II期工作奠定基础，以优化预期的双重抑制剂先导化合物，使其成为临床候选药物：目标（任务）#1。确定TP化合物抑制BRD4的构效关系（SAR）。方法：合成30个TP化合物并测定其BRD4和PI-3K抑制谱。目标（任务）#2。开发预测计算BRD4模型，用于设计化合物的计算机对接。方法：改变BRD4模型的分子硅拟合参数，直到TP数据集的对接预测与实际的BRD4测定结合结果相关，从而创建一个有效的对接模型。目标（任务）#3。确定BRD4/PI-3K双重抑制对MYC的影响和治疗指标。方法：测定MYC表达和活性水平，并比较暴露于单一BRD4或PI-3K与双重BRD4/PI-3K抑制条件下对癌细胞系和正常细胞系的毒性。这项研究的贡献在于它提供了一种有效的机制来阻断MYC活性，MYC活性驱动癌症，这将是重要的，因为它将允许增强MYC依赖性癌症的联合治疗，如CLL、髓母细胞瘤和神经母细胞瘤。这种方法是创新的，因为它使用两种正交机制和一种化合物来攻击一个关键的癌症靶点，它挑战了在没有FDA批准的治疗领域的癌症研究中普遍存在的忽视成本的一种药物一种靶点的疗效限制心态。