NuPeak Therapeutics Inc. is a biotechnology start-up company (C corporation) designed to deliver a first-in- class small-molecule kinase inhibitor. The present Project is aimed at an inhibitor for treatment of breast cancer, which remains a leading cause of morbidity and mortality in the U.S. despite current therapeutic approaches. In that context, we identified a novel type 2 immune response that activates mitogen-activated protein kinase 13 (MAPK13) to drive epithelial progenitor-stem cell metaplasia in the airway. We reasoned that the findings might be relevant to reports of type 2 immune activation and MAPK13 function in carcinomas. In particular, MAPK13 expression correlates with decreased survival in breast cancer, and MAPK13 gene knockdown and knockout attenuates breast cancer cell growth in vitro and in vivo. Moreover, MAPK13 function was independent of estrogen-receptor (ER), progesterone-receptor (PR), or ERBB2/HER2 status, suggesting relevance to ER-PR- HER2-negative (triple-negative) breast cancers. However, to our knowledge, there were no MAPK13 inhibitors available to test this application. In that regard, we obtained the first x-ray crystal structure of MAPK13 and used structure-based drug design to develop the first small-molecule inhibitors of MAPK13. We since performed additional medicinal chemistry to generate proprietary chemical analogs that show marked increases in potency and selectivity and form the basis for approved and pending patents. Our Preliminary Studies show that these new inhibitors block proliferation of luminal hormone-receptor-positive and basal-like triple-negative breast cancer cells in culture and identify a lead compound that inhibits cell growth at concentrations (GI50=44 nM) that are nontoxic and compare favorably with approved kinase inhibitors. This lead also demonstrates favorable results from MAPK13 enzyme assay (IC50=9 nM), kinase selectivity assays, physical-chemical property assessments, ADMET microsomal stability and cell permeability assays, and pharmacokinetic (PK) analysis for oral dosing in vivo. Thus, we propose a Phase I STTR program for investigators at NuPeak and Washington University to advance this lead through Specific Aims that evaluate the lead in controlling breast cancer cell lines in cell culture (Aim 1) and after subcutaneous xenotransplantation or intravenous injection of these cell lines in mice (Aim 2). NuPeak will operate with the entrepreneurial resources of BioGenerator St Louis and CORTEX biotech district and a quick-license from Washington University under patents for the lead and related proprietary compounds. The commercialization strategy will be based on establishing initial efficacy and nontoxicity of a lead compound in relation to MAPK13 expression and activation in Phase 1 STTR studies, further development towards IND status and initial safety clinical trials in Phase 2 STTR studies, and then more advanced clinical trials and FDA approval in partnership with the pharmaceutical industry. Thus, we expect Phase 1 STTR to provide the basis for pursuit of additional data in Phase 2 aimed at GMP protocols, further non-GLP and GLP safety and toxicity studies, and Phase I-IIA clinical trials of a first-in-class MAPK13 inhibitor in humans.
Cancer is a leading cause of morbidity and mortality in the U.S. despite current therapeutic approaches. In particular, invasive breast cancer cases develop at 266,000 per year and result in 46,000 deaths for 2017. The proposed development of a new anti-cancer drug that is safe and effective will thereby address an unmet need for a major public health problem.