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 rele...