Novel STAT3 inhibitor for overcoming chemoresistant ovarian cancer .

用于克服化疗耐药性卵巢癌的新型 STAT3 抑制剂。

基本信息

批准号：
10547366
负责人：
Ali Rayet Ozes
金额：
$ 39.99万
依托单位：
ALTAY THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10547366
关键词：
Address Animals Area BCL2L1 gene Benchmarking Binding Binding Sites Biological Assay Cancer cell line Carboplatin Cause of Death Cell Line Cells Chemoresistance Cisplatin Clinic Clinical Cyclin D1 DNA DNA Binding DNA Binding Domain Development Diagnosis Dimerization Disease Epithelial ovarian cancer FDA approved Gene Expression Profile Genes Genetic Transcription Genetically Engineered Mouse Grant Histologic Histopathology Human In Vitro Indiana Inflammation Inflammatory Lead Malignant Female Reproductive System Neoplasm Malignant neoplasm of ovary Mammalian Oviducts Measures Methods Modeling Molecular Mus Neoadjuvant Therapy Neoplasm Metastasis Oncogenic Operative Surgical Procedures Paclitaxel Pathway interactions Patient Selection Patient-Focused Outcomes Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phenotype Phosphorylation Physiological Plasma Platinum Primary Neoplasm Property Proteins RNA Recurrence Resistance Role STAT1 gene STAT3 gene Small Business Innovation Research Grant Specificity Surface Testing Therapeutic Transgenic Mice Tumor Debulking United States Universities Up-Regulation Validation Vegf Inhibitor Woman Xenograft Model Xenograft procedure base bioluminescence imaging cancer cell cell growth cell motility chemotherapy clinical application commercialization culture plates cytotoxicity drug development effective therapy experience improved in silico in vivo in vivo Model inhibitor intraperitoneal lead candidate medical schools nanomolar neoplastic cell novel novel strategies novel therapeutic intervention novel therapeutics protein protein interaction screening simulation small hairpin RNA small molecule synergism therapeutic target transcription factor translational impact treatment strategy tumor tumor progression

项目摘要

Abstract/Summary Epithelial ovarian cancer (OC) is the fifth leading cause of death in women and the most lethal gynecological malignancy in the United States. OC is mostly diagnosed at an advanced stage. Patients undergo debulking surgery and chemotherapy or neoadjuvant chemotherapy and interval debulking surgery. Conventional drugs are carboplatin and paclitaxel. Despite the recent introduction of FDA-approved PARP- and VEGF-inhibitors for OC, the vast majority of patients will experience disease recurrence that requires additional treatment and recurrent OC is essentially incurable. New therapeutics to improve patient outcomes are needed. Transcriptional profiles have demonstrated that the master transcriptional regulator STAT3 to be highly active in OC, determined by increased phosphorylation in SH2-dimerization domain (pSTAT3-Y705) and induction of oncogenic factors. Active STAT3 in metastatic and chemoresistant OC correlates with poor patient survival, and inhibiting STAT3 with shRNA, or small molecules inhibited OC progression, supporting the objective of targeting STAT3 as a viable therapeutic strategy. Additionally, we demonstrate significant upregulation of STAT3 activity in OC cells is strongly associated with increased platinum resistance. We hypothesize that targeting STAT3 will block multiple oncogenic pathways and sensitize OC cells to chemotherapy. Although transcriptions factors (TF) like STAT3 are attractive therapeutic targets, TFs are challenging to target with small molecules due to lack of clear small molecule binding pockets, large surface areas important for protein-protein interactions and large intrinsically disordered domains. At Altay Therapeutics, we developed a platform that enables identification of small molecule binding pockets within intrinsically disordered domains in previously undruggable TFs, allowing a novel approach for specific targeting of STAT3 and development of potent STAT3 inhibitors (STAT3i). Using our platform, we identified inhibitors that reduced STAT3 DNA binding by targeting the disordered DNA binding domain. Importantly, these STAT3i have minimal STAT1 inhibitory activity, low cytotoxicity and when used in combination with CDDP, synergized and increased platinum sensitivity across OC cell lines. We propose three aims based on quantitative metrics that will clearly define the top candidate(s) which inhibit STAT3 compared to existing STAT3is and block OC progression. In Aim 1, we will determine STAT3 target gene inhibition and measure effects on secreted inflammatory factors with Altay’s novel STAT3is. In Aim 2, we will carry out in vitro phenotypic studies with human and transgenic mouse OC cells using STAT3is in combination with platinum chemotherapy. In Aim 3, we will determine antitumor activity of STAT3i using OC cells in orthotopic and intraperitoneal in vivo models alone and in combination with platinum chemotherapy. The proposed studies will establish the potential for targeting STAT3 in treating chemoresistant OC and guide new therapeutic strategies in this setting. We will then pursue an SBIR phase 2 grant that will include medicinal chemistry efforts and additional animal studies and ultimately commercialization of a first-in-class STAT3 inhibitor for OC.

摘要/摘要上皮卵巢癌（OC）是妇女的第五大死亡原因，也是最致命的妇科。美国的恶性肿瘤。 OC主要在高级阶段被诊断出。患者进行了延期手术和化学疗法或新辅助化学疗法和间歇性延迟手术。常规药物是卡铂和紫杉醇。尽管最近引入了FDA批准的PARP和VEGF抑制剂 OC，绝大多数患者会经历需要额外治疗的疾病复发，并且反复发生的OC基本无法治愈。需要新的疗法来改善患者预后。转录配置文件表明，主转录调节剂STAT3在OC中高度活跃，确定通过增加SH2-二聚体结构域（PSTAT3-Y705）的磷酸化以及致癌因子的诱导。转移性和化学抗性OC中的活性STAT3与患者的生存不良相关，并抑制STAT3 用shRNA或小分子抑制了OC的进展，支持将STAT3作为A的目标可行的理论策略。此外，我们证明了OC细胞中STAT3活性的显着上调与铂耐药性的增加密切相关。我们假设目标STAT3将阻止多种致癌途径和对化学疗法的敏感性OC细胞。虽然转录因子（TF）喜欢 STAT3是有吸引力的治疗靶标，由于缺乏清晰的分子，TF挑战了针对小分子的靶标小分子结合口袋，对蛋白质 - 蛋白质相互作用重要的大表面积和大的表面积本质上无序的域。在Altay Therapeutics，我们开发了一个平台，可以识别在以前不可用的TF中，本质上无序的域内的小分子结合袋，允许一种新型的STAT3特异性靶向方法和潜在STAT3抑制剂的发展（STAT3I）。使用我们的平台，我们确定了通过靶向无序DNA结合来降低STAT3 DNA结合的抑制剂领域。重要的是，这些STAT3I具有最小的STAT1抑制活性，低细胞毒性，当与CDDP结合使用，在OC细胞系之间协同和增加铂敏感性。我们提出了三个目的基于定量指标，这些指标将明确定义最高候选者，该候选人抑制了STAT3与现有的STAT3IS和BLOCK OC进展。在AIM 1中，我们将确定STAT3靶基因抑制和 Altay的新型STAT3IS对分泌炎症因子的影响效果。在AIM 2中，我们将在体外进行使用STAT3I与铂联合使用人类和转基因小鼠OC细胞的表型研究化学疗法。在AIM 3中，我们将使用OC细胞在原位性和腹膜内的体内模型并与铂化学疗法结合使用。拟议的研究将确定针对STAT3治疗化学耐药性OC并指导新的治疗策略的潜力在这种情况下。然后，我们将寻求SBIR 2阶段赠款，其中包括药物化学工作和其他动物研究以及最终对OC的第一类STAT3抑制剂进行商业化。