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: 9526454
• 负责人: Guillermo A Morales
• 金额: $ 64.77万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9526454
• 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; 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; Proto-Oncogene Proteins c-myc; 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.

抑制关键的癌症促进转录因子MYC（c-MYC和MYCN）的需求尚未得到满足。 其作用于许多细胞受体下游，并通过信号转录途径激活癌细胞基因 抵抗和肿瘤生长。迄今为止，MYC的小分子抑制剂仍然难以捉摸。在我们的第一阶段 STTR（CA 192656），我们开发了一种先导化合物SF 2523， 通过阻断PI-3激酶（PI-3 K）和表观遗传高度显性调节因子， 机械，BRD 4.本申请的目的是通过先进的临床前研究开发SF 2523。 本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亚组中过表达，导致对PI-3 K和其他药物的耐药性。 信号通路抑制剂。MYC和PI-3 K都是公认的癌蛋白， 在许多肿瘤类型中的驱动因素。此外，BRD 4正在迅速成为占主导地位的表观遗传因子 转录组和癌细胞对激酶抑制的抗性的调节剂。因此，一般 在癌症生物学竞技场中的共识是，BRD 4和/或MYC的抑制应该证明在多种癌症中是有益的。 其中MYC是肿瘤细胞转化和抗性的既定调节剂的癌症。我们的创新 该方法基于我们的中心假设，即PI-3 K/BRD 4双重抑制剂SF 2523将有效抑制MYC 通过PI-3 K抑制增强其降解并通过BRD 4阻断MYC转录活性来抑制MYC活性 抑制作用 我们的第一阶段STTR特定目标成功地解决了SF 2523在活性位点的晶体结构， BRD 4，并确定由以下设计的双重PI-3 K/BRD 4抑制剂的结构活性关系： 验证了分子建模研究，并证明了我们的双靶向单一抑制剂与 使用两种不同抑制剂的累积毒性。我们成功的第一阶段研究为我们的 选择SF 2523作为临床前开发的候选药物，用于治疗PI-3 K/MYC依赖性恶性肿瘤 作为临床开发策略进行I期试验。 该II期提案的重要性在于，它将通过临床前开发推进SF 2523， 验证了这种新型PI-3 K/BRD 4双重抑制剂作为候选药物对抗PI-3 K/MYC驱动的恶性肿瘤， 高死亡率，例如肝细胞癌（HCC）和头颈部鳞状细胞癌 （SCCHN），并通过进一步评价从I期SAR中发现的SF 2523类似物获得备用候选物 问题研究此外，我们在第二阶段的目标将确定PI-3 K和MYC肿瘤的签名和伴侣， 诊断方法，将定义对SF 2523的敏感性，因为我们正在向FDA注册， 这一“同类第一”双重PI-3 K/BRD 4抑制剂化学型在癌症治疗中的商业化。