Development of the first-in-class novel dual PI-3K/BRD4 inhibitor SF2523

开发一流的新型双重 PI-3K/BRD4 抑制剂 SF2523

• 批准号: 9348077
• 负责人: Guillermo A Morales
• 金额: $ 132.06万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348077
• 关键词: 1-Phosphatidylinositol 3-Kinase; Academia; Active Sites; Adult; Alcohols; Animals; Automobile Driving; Award; BAY 54-9085; Back; Binding Sites; Blood; Cancer Biology; Catalytic Domain; Cells; Childhood; Childhood Solid Neoplasm; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Computer Simulation; Consensus; Crystallization; Data; Development; Dose; Epigenetic Process; Evaluation; Excipients; Exposure to; Formulation; Genetic Transcription; Goals; Growth; Head and Neck Squamous Cell Carcinoma; Human; Industry; Lead; Lysine; MAP Kinase Gene; MYCN gene; Malignant Childhood Neoplasm; Malignant Epithelial Cell; Malignant Neoplasms; Maximum Tolerated Dose; Mission; Modeling; Molecular Models; Morbidity - disease rate; Mus; Mutation; Neuroblastoma; Normal Cell; Oncogenes; Oncoproteins; Oral; PIK3CA gene; Particle Size; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphotransferases; Play; Primary carcinoma of the liver cells; Public Health; Ras/Raf; Rattus; Receptor Cell; Receptor Signaling; Research; Resistance; Route; Safety; Schedule; Signal Pathway; Small Business Technology Transfer Research; Structure; Structure-Activity Relationship; Study models; Subgroup; Technology; Therapeutic; Therapeutic Studies; Toxic effect; United States National Institutes of Health; Viral; analog; base; c-myc Genes; cancer cell; cell transformation; clinical candidate; clinical development; commercialization; companion diagnostics; design; disability; drug candidate; efficacy study; improved; inhibitor/antagonist; innovation; insight; kinase inhibitor; knock-down; medulloblastoma; molecular modeling; mortality; neoplastic cell; novel; novel therapeutics; overexpression; phase 1 study; phase I trial; pre-clinical; preclinical development; preclinical study; prognostic significance; response; safety study; scale up; single molecule; small molecule; small molecule inhibitor; technology development; therapeutic target; transcription factor; transcriptome; tumor; tumor growth; tumorigenesis

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 and tumor growth. To date, small molecule inhibitors of MYC have remained elusive. In our Phase I STTR (CA192656), 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. The objective of this application will be to develop SF2523 through advanced preclinical studies for therapeutic application in this Phase II STTR proposal. The transcription factor, MYC (c-MYC and MYCN) plays a key role in cancer growth, proliferation, survival, and 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 blocking MYC transcriptional activity via BRD4 inhibition. Our Phase I STTR Specific Aims successfully solved the crystal structure of SF2523 in the active site of BRD4 and determine the structure activity relationships 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 successful Phase I studies set the stage for our selection of SF2523 as the candidate for preclinical development to treat PI-3K/MYC dependent malignancies in Phase I trials as a clinical development strategy. The significance of this Phase II proposal is that it will advance SF2523 through preclinical development and validate this novel dual PI-3K/BRD4 inhibitor as a 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 a back-up candidate by further evaluation of SF2523 analogs found from Phase I SAR studies. Moreover, our aims in Phase II will identify PI-3K and MYC tumor signatures and a companion diagnostic approach which will define sensitivity to SF2523 as we move toward FDA registration and commercialization of this “first in class” dual PI-3K/BRD4 inhibitor chemotype in 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 I 期研究中仍然难以捉摸。 STTR (CA192656)，我们开发了一种先导化合物 SF2523，它表现出有效的正交抑制作用 通过阻断 PI-3 激酶 (PI-3K) 和表观遗传学的高度显性调节因子来对抗 MYC 活性 该应用的目标是通过先进的临床前开发 SF2523。 该 II 期 STTR 提案中的治疗应用研究。 转录因子 MYC（c-MYC 和 MYCN）在癌症生长、增殖、存活、 它在大多数人类癌症的一个亚组中过度表达，导致对 PI-3K 和其他癌症产生耐药性 MYC 和 PI-3K 都是已得到证实的信号通路抑制剂。 此外，BRD4 正在迅速成为主要的表观遗传因素。 转录组和癌细胞对激酶抑制的抵抗力的调节因子。 癌症生物学领域达成共识，抑制 BRD4 和/或 MYC 应证明对多种疾病有益。 MYC 是肿瘤细胞转化和耐药性的既定调节剂。 该方法以我们的中心假设为中心，即双重 PI-3K/BRD4 抑制剂 SF2523 将有效抑制 MYC 通过抑制 PI-3K 增强其降解并通过 BRD4 阻断 MYC 转录活性来增强其活性 抑制。 我们的第一阶段 STTR 具体目标成功解决了 SF2523 活性位点的晶体结构 BRD4 并确定双 PI-3K/BRD4 抑制剂周围的结构活性关系 验证了分子模型研究，并证明了我们的双靶向单一抑制剂与 使用两种单独抑制剂的累积毒性为我们的成功的第一阶段研究奠定了基础。 选择 SF2523 作为临床前开发候选药物，用于治疗 PI-3K/MYC 依赖性恶性肿瘤 作为临床开发策略进行 I 期试验。 该二期提案的意义在于，它将通过临床前开发和临床前开发来推进SF2523的发展。 验证这种新型双重 PI-3K/BRD4 抑制剂作为针对 PI-3K/MYC 驱动的恶性肿瘤的候选药物 高死亡率，例如肝细胞癌 (HCC) 和头颈部鳞状细胞癌 (SCCHN) 并通过进一步评估第一阶段 SAR 中发现的 SF2523 类似物获得后备候选药物 此外，我们第二阶段的目标是确定 PI-3K 和 MYC 肿瘤特征及其伴随物。 随着我们向 FDA 注册迈进，该诊断方法将定义对 SF2523 的敏感性 这种“一流”双重 PI-3K/BRD4 抑制剂化学型在癌症治疗中的商业化。