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

项目名称：开发Mnk1/2降解剂，VNLG-152作为治疗三阴乳症的新方法 癌 项目摘要/摘要 目前，对于三阴性(ER、α、PR和HER2阴性)的患者还没有有效的治疗方法 癌症(TNBC)，一种侵袭性和高转移性疾病。真核细胞起始因子4E(EIF4E)的激活 丝裂原活化蛋白激酶(MAPK)相互作用的蛋白激酶1和2(Mnk1/2)在细胞的发育过程中起着关键作用。 TNBC的进展和转移。值得注意的是，Mnk1/2的活性和蛋白的磷酸化 EIF4E对于正常发育是必不可少的，因此使Mnk1/2成为有吸引力的治疗靶点。我们有 最近显示，专利异戊二烯制药公司(IPI)新型维甲酰胺(NRS)表现出精致的抗 TNBC体内外抗MDA-MB-231肿瘤移植瘤、转移及患者来源的活性 小鼠异种移植(PDX)。为了将这些发现转化为人类临床试验，我们已经确定了一种新的 化合物，外消旋VNLG-152(VNLG-152R)，以及三个支持化合物(VNLG-153，VNHM-1-73和VNHM- 1-81)导致Mnk1/2降解(从而导致致癌基因peIF4E的耗尽)。通过靶向Mnk1/2蛋白 在降解过程中，VNLG-152R有效地抑制MNK-eIF4E和mTORC1信号通路并强烈调节 下游因素涉及细胞周期调控、细胞凋亡、促炎细胞因子/趋化因子分泌、 上皮-间充质转化(EMT)与转移最重要的是，口服生物利用度VNLG-152R显示 显著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 证明用一种有效的Mnk1/2降解剂VNLG-152R靶向MNK-eIF4E/mTORC1信号转导是一种新的方法 可作为单一疗法开发的治疗策略，用于有效治疗两种原发疾病 和转移性TNBC。在马里兰创新创始(MII)奖的支持下，我们成功地完成了 我们的SBIR第一阶段研发研究的所有目标，以及进行了许多没有 原本就在预料之中。我们现在寻求直接到第二阶段的SBIR支持，以推动VNLG-152R通过各种IND- 促进临床前开发活动。我们的目标是开发VNLG-152R作为口服靶向抗癌剂 用于有效治疗难治性原发和转移性TNBC。 这项直接到第二阶段的SBIR提案的具体目标是： 1.合成300克非GMP VNLG-152R用于临床前研究，包括分析表征， 配制并使用该制剂支持GLP的临床前研究。 2.利用TNBC的体内外模型，对VNLG-152R进行辅助药理实验。 3.进行支持IND的研究，包括在两个相关动物物种中进行GLP毒性和毒物动力学研究 确定用于人类第一阶段临床试验的合适的VNLG-152R起始剂量，并准备 IND的文件。 在成功完成这些研究后，将提交FDA研究新药(IND)申请。

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.