NuPeak Therapeutics Inc. is a biotechnology company (C corporation) designed to deliver a first-in-class small- molecule kinase inhibitor (SMKI) for therapeutic use in humans. The present Project is aimed at an inhibitor for treatment of respiratory airway disease especially due to asthma and COPD, which remain leading causes of morbidity and mortality in the U.S. and worldwide despite current therapeutic approaches. Moreover, there is growing recognition that these diseases are linked to obstruction of the airways with inflammatory mucus. In that context, we identified a novel type 2 immune response that activates mitogen-activated protein kinase 13 (MAPK13) to drive airway progenitor epithelial cells (APECs) to mucous cells in cell and animal models. This mechanism was validated in patients with excess mucus production due to asthma and COPD by our lab and by others, suggesting the therapeutic benefit of a MAPK13 or combined MAPK13-14 inhibitor that also blocks the conventional immune response. However, to our knowledge, no MAPK13 or MAPK13-14 inhibitors are yet available. Accordingly, we obtained the first x-ray crystal structure of MAPK13 and used structure-based drug design to develop the first MAPK13 inhibitors. Preliminary Studies define proprietary chemical analogs that form the basis for our approved and pending patents for MAPK13 and MAPK13-14 inhibitors and uses thereof. Among these compounds, we identify a lead Compound 396 with highly favorable qualities for enzyme inhibition (MAPK13 IC50=14 nM; MAPK14 IC50=7 nM), binding mechanism (DFG-out) and kinetics (slow Kon and Koff and low KD=2.1x10-13 M), kinome selectivity, and physical-chemical properties. Moreover, Compound 396 effectively and safely blocks IL-13-stimulated inflammatory mucin (MUC5AC) production at low nontoxic concentrations (IC50=0.05 nM; cell therapeutic index=20,000) in primary-culture human airway epithelial cells. Further, Compound 396 exhibits excellent microsomal stability and cell permeability in vitro and pharmacokinetic characteristics in vivo for oral dosing. In addition, Compound 396 safely attenuates inflammatory mucus production after IL-13 challenge in a pig in vivo model and after respiratory viral infection in pig and mouse in vivo models. Thus, we propose a Phase I STTR program for investigators at NuPeak and Washington University to advance Compound 396 to the next phase of pharmacology and toxicology testing (Aim 1) and Chemistry, Manufacturing, and Control (CMC) information (Aim 2) needed for IND publication. NuPeak will operate with the entrepreneurial resources of the BioGenerator venture fund and a quick-start license from Washington University under patents that cover the synthesis and use of MAPK13 and MAPK13-14 inhibitors, including Compound 396 and back-ups such as Compound 397. The commercialization strategy will be based on establishing initial pharmacology-toxicology and chemistry-manufacturing-control (CMC) information in Phase 1 STTR, then final testing, IND publication, and Phase 1 safety clinical trials in healthy humans in Phase 2 STTR, and then more advanced clinical trials and FDA approval in Phase 3 STTR.
Public Health Relevance Statement: Relevance Excess airway mucus production is one of the most common maladies of mankind, and the condition may be life-threatening for patients with chronic lower respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). At present, there are no specific and effective drugs to control excess airway mucus production. The proposed development of an anti-mucus drug will thereby address an unmet need for a major public health problem.
Project Terms: Acute; Address; Affinity; Airway Disease; airway obstruction; analog; Animal Model; Asthma; Attenuated; attenuation; Back; base; Binding; Biotechnology; Canis familiaris; Cell model; Cells; chemical property; Chemicals; Chemistry; Chinese Hamster Ovary Cell; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Trials; commercialization; Crystallization; Data Analyses; Data Set; design; Development; Disease; Dose; Drug Design; effective therapy; efficacy trial; Enzyme Inhibition; Epithelial Cells; Exhibits; Family suidae; Feedback; Formulation; Funding; Goals; Guidelines; Host Defense; Human; Immune response; improved; In Vitro; in vivo; in vivo Model; Inflammatory; inhibitor/antagonist; Interleukin-1; Interleukin-13; Investigational Drugs; kinase inhibitor; Kinetics; Lead; Legal patent; Licensing; Life; Ligands; Link; Lung diseases; MAPK13 gene; MAPK14 gene; Maximum Tolerated Dose; Micronucleus Tests; Morbidity - disease rate; mortality; MUC5AC gene; Mucins; Mucociliary Clearance; Mucous body substance; Mus; National Heart, Lung, and Blood Institute; novel; off-patent; Oral; Patients; Permeability; Pharmaceutical Preparations; pharmacokinetic characteristic; Pharmacology and Toxicology; Phase; Plethysmography; Preclinical Testing; Process; Production; progenitor; programs; Public Health; Publications; pulmonary function; Rattus; Research Personnel; Resources; respiratory; Roentgen Rays; Route; Safety; Small Business Technology Transfer Research; small molecule; Structure; Testing; Therapeutic; Therapeutic Index; Therapeutic Uses; TNF gene; Universities; Viral Respiratory Tract Infection; Washington
