Development of VNLG-152R as novel therapeutic for triple negative breast cancer

开发 VNLG-152R 作为三阴性乳腺癌的新型疗法

• 批准号: 10474986
• 负责人: VINCENT Collins Ofuka NJAR
• 金额: $ 99.51万
• 依托单位: ISOPRENE PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474986
• 关键词: Ames Assay; Animals; Antineoplastic Agents; Apoptosis; Award; Back; Biological Testing; Breast Cancer Model; Canis familiaris; Cardiovascular system; Cell Cycle Regulation; Cell Line; Clinical Pharmacology; Clinical Trials; Data; Development; Disease; Dose; Drug Kinetics; Epithelial; Estrogen Receptor alpha; Eukaryotic Initiation Factor-4E; Evaluation; Exhibits; Formulation; Funding; Genetic; Goals; Growth; Hepatocyte; Human; In Vitro; Inflammatory; Investigational Drugs; Investigational New Drug Application; Isoprene; Legal patent; Liver; MAP Kinase Gene; MDA MB 231; Manuscripts; Maryland; Mesenchymal; Methods; Micronucleus Tests; Mitogen-Activated Protein Kinases; Molecular; Mus; Neoplasm Metastasis; Oncogenic; Oral; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Phosphorylation; Phosphotransferases; Play; Preparation; Publications; Rattus; Reporting; Role; Safety; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Sodium Chloride; Survival Rate; Technology; Testing; Therapeutic; TimeLine; Toxic effect; Toxicity Tests; Toxicokinetics; Toxicology; Translating; Validation; Woman; Writing; Xenograft Model; Xenograft procedure; analytical method; cancer recurrence; cancer type; chemokine; clinical development; commercialization; cytokine; effective therapy; feasibility testing; first-in-human; in vitro activity; in vivo; in vivo Model; innovation; malignant breast neoplasm; meetings; method development; novel; novel therapeutic intervention; novel therapeutics; overexpression; patient derived xenograft model; pre-clinical; preclinical development; preclinical study; programs; protein degradation; research and development; respiratory; retinamide; scale up; small molecule; solid state; stability testing; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor xenograft

Project Title: Development of Mnk1/2 Degrader, VNLG-152 as Novel Therapeutic for Triple Negative Breast Cancer PROJECT SUMMARY/ABSTRACT Currently, there are no effective therapies for patients with triple negative (ERα, PR, and Her2 negative) breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. It is important to note that Mnk1/2 activity and the phosphorylation of eIF4E are dispensable for normal development, thus making Mnk1/2 attractive therapeutic targets. We have recently shown that proprietary Isoprene Pharmaceuticals Inc. (IPI) novel retinamides (NRs) exhibit exquisite anti- TNBC activities in vitro and in vivo against MDA-MB-231 tumor xenografts, metastasis and TNBC patient-derived xenografts (PDX) in mice. To translate these findings towards human clinical trials, we have identified novel compounds, racemic VNLG-152 (VNLG-152R), with three back-up compounds (VNLG-153, VNHM-1-73 and VNHM- 1-81) that induce Mnk1/2 degradation (with consequent depletion of oncogenic peIF4E). By targeting Mnk1/2 protein degradation, VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulates downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable dose-dependent antitumor (91 to 100% growth inhibition) and antimetastatic (~80% inhibition) activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for the effective treatment of patients with both primary and metastatic TNBC. With support from Maryland Innovative Initiation (MII) award we have successfully completed all the aims of our SBIR Phase-1-type R&D study as well as conducted many additional studies that were not originally anticipated. We now seek Direct-to-Phase II SBIR support to advance VNLG-152R through various IND- enabling pre-clinical development activities. Our goal is to develop VNLG-152R as an oral targeted anticancer agent for effective treatment of the difficult-to-treat primary and metastatic TNBC. The specific aims for this Direct-to-Phase II SBIR proposal are: 1. Synthesize 300 g of non-GMP VNLG-152R for preclinical studies, including analytical characterization, formulation and use this agent to support GLP preclinical studies. 2. Conduct ancillary pharmacology with VNLG-152R using in vitro and in vivo models of TNBC. 3. Conduct IND-enabling studies, including GLP toxicity and toxicokinetics studies in two relevant animal species to identify appropriate starting VNLG-152R dose for use in first-in-human Phase I clinical trials and prepare the IND filing. Upon successful completion of these studies an FDA Investigational New Drug (IND) application will be filed.

项目名称：开发 Mnk1/2 降解剂 VNLG-152 作为三阴性乳腺癌的新型治疗药物 癌症 项目概要/摘要 目前，对于三阴性（ERα、PR 和 Her2 阴性）乳腺患者尚无有效的治疗方法 癌症（TNBC），一种侵袭性和高度转移性疾病。真核起始因子 4E (eIF4E) 的激活 丝裂原激活蛋白激酶 (MAPK) 相互作用激酶 1 和 2 (Mnk1/2) 在发育中发挥关键作用， TNBC 的进展和转移。值得注意的是 Mnk1/2 活性和磷酸化 eIF4E 对于正常发育来说是不可或缺的，因此 Mnk1/2 成为有吸引力的治疗靶点。我们有 最近表明，专有的 Isoprene Pharmaceuticals Inc. (IPI) 新型视黄酰胺 (NR) 具有出色的抗- TNBC 体外和体内针对 MDA-MB-231 肿瘤异种移植物、转移和 TNBC 患者来源的活性 小鼠异种移植物（PDX）。为了将这些发现转化为人体临床试验，我们发现了新的 化合物，外消旋 VNLG-152 (VNLG-152R)，具有三种备用化合物（VNLG-153、VNHM-1-73 和 VNHM- 1-81) 诱导 Mnk1/2 降解（随之而来的是致癌 peIF4E 的耗尽）。通过靶向 Mnk1/2 蛋白 VNLG-152R 有效抑制 Mnk-eIF4E 和 mTORC1 信号通路并强烈调节 参与细胞周期调节、细胞凋亡、促炎细胞因子/趋化因子分泌的下游因子， 上皮间质转化（EMT）和转移。最重要的是，口服生物可利用的 VNLG-152R 表现出 显着的剂量依赖性抗肿瘤（91% 至 100% 生长抑制）和抗转移（~80% 抑制）活性 针对细胞系和患者来源的 TNBC 异种移植模型，没有明显的宿主毒性。总的来说，这些研究 证明用有效的 Mnk1/2 降解剂 VNLG-152R 靶向 Mnk-eIF4E/mTORC1 信号传导是一种新型的 可以开发为单一疗法的治疗策略，以有效治疗原发性和 和转移性 TNBC。在马里兰州创新启动 (MII) 奖的支持下，我们成功完成了 我们的 SBIR 第一阶段型研发研究的所有目标，以及进行了许多其他研究，这些研究没有 原本预计的。我们现在寻求直接进入 II 期 SBIR 支持，以通过各种 IND-推进 VNLG-152R 促进临床前开发活动。我们的目标是开发 VNLG-152R 作为口服靶向抗癌药物 用于有效治疗难以治疗的原发性和转移性 TNBC。 该直接进入第二阶段 SBIR 提案的具体目标是： 1. 合成 300 g 非 GMP VNLG-152R 用于临床前研究，包括分析表征， 制剂并使用该药物支持 GLP 临床前研究。 2. 使用 TNBC 的体外和体内模型，用 VNLG-152R 进行辅助药理学。 3. 进行 IND 支持的研究，包括两个相关动物物种的 GLP 毒性和毒代动力学研究 确定用于首次人体 I 期临床试验的适当起始 VNLG-152R 剂量并准备 IND 申请。 成功完成这些研究后，将向 FDA 提交新药研究 (IND) 申请。