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

项目名称：开发Mnk 1/2降解剂VNLG-152作为三阴性乳腺癌的新型治疗剂 癌 项目总结/摘要 目前，对于三阴性（ERα、PR和Her 2阴性）乳腺癌患者没有有效的治疗方法。 癌症（TNBC），一种侵袭性和高转移性疾病。真核起始因子4 E（eIF 4 E）的激活 丝裂原活化蛋白激酶（MAPK）相互作用激酶1和2（Mnk 1/2）在发育中起关键作用， TNBC的进展和转移。重要的是要注意，Mnk 1/2活性和磷酸化 eIF 4 E是正常发育所必需的，因此使Mnk 1/2成为有吸引力的治疗靶点。我们有 最近显示，专有的异戊二烯制药公司。(IPI)新的视黄酰胺（NR）表现出精细的抗- 体外和体内TNBC对MDA-MB-231肿瘤异种移植物、转移和TNBC患者源性肿瘤的活性 异种移植物（PDX）中的细胞毒性。为了将这些发现转化为人类临床试验，我们已经确定了新的 化合物，外消旋VNLG-152（VNLG-152 R），以及三种备用化合物（VNLG-153、VNHM-1-73和VNHM-1 - 73）。 1-81），其诱导Mnk 1/2降解（随后消耗致癌peIF 4 E）。通过靶向Mnk 1/2蛋白 VNLG-152 R有效抑制Mnk-eIF 4 E和mTORC 1信号通路，并强烈调节Mnk-eIF 4 E和mTORC 1的降解。 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素， 上皮-间质转化（EMT）和转移。最重要的是，口服生物可利用的VNLG-152 R表现出 显著的剂量依赖性抗肿瘤（91 - 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异种移植物模型，没有明显的宿主毒性。总的来说，这些研究 证明用有效的Mnk 1/2降解剂VNLG-152 R靶向Mnk-eIF 4 E/mTORC 1信号传导是一种新的 治疗策略，可开发为单药治疗，用于有效治疗原发性 和转移性TNBC。在马里兰州创新启动（MII）奖的支持下，我们成功地完成了 我们的SBIR阶段1型研发研究的所有目标，以及进行了许多额外的研究， 最初预计。我们现在寻求直接到第二阶段SBIR支持，通过各种IND推进VNLG-152 R， 开展临床前开发活动。我们的目标是开发VNLG-152 R作为口服靶向抗癌剂 用于有效治疗难治性原发性和转移性TNBC。 本直接至第II阶段SBIR提案的具体目标是： 1.合成300 g非GMP VNLG-152 R用于临床前研究，包括分析表征， 制剂，并使用该试剂支持GLP临床前研究。 2.使用TNBC的体外和体内模型用VNLG-152 R进行辅助药理学。 3.开展IND使能研究，包括两种相关动物种属的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-152 R剂量，并准备 IND文件。 在成功完成这些研究后，将提交FDA研究性新药（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.