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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

基本信息

批准号：
10254684
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
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254684
关键词：
Ames Assay Animals Antineoplastic Agents Apoptosis Award Back Bioavailable 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

项目摘要

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：Mnk1/2降解剂VNLG-152治疗三阴性乳腺的研究