A New Small-Molecule Kinase Inhibitor for Airway Disease

Title
A new small-molecule kinase inhibitor for airway disease
Summary
NuPeak Therapeutics Inc. is a biotechnology company (C corporation) designed to deliver a first-in-class small-
molecule kinase inhibitor for therapeutic use in humans. The present project is aimed at the next steps to develop
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 airway inflammation and mucus production in
response to respiratory viruses, allergens, or toxins. In that context, we identified a mitogen-activated protein
kinase (MAPK) known as MAPK13 that drives the key features of respiratory airway disease in human cell and
animal models. We also validated critical components of this pathway in asthma, COPD and long-term Covid-
19, suggesting the therapeutic benefit of a MAPK13 inhibitor in these patient populations. Further, this relatively
orphan kinase was dismissed in favor of conventional inflammatory signals and was untargeted in previous
kinase-inhibitor screens. Therefore, we used structure-based drug design to engineer proprietary small-molecule
kinase inhibitors against MAPK13 and arrived at a lead candidate compound (NuP-4A) based on physical-
chemical attributes, cell safety, enzyme inhibition, binding mechanism, interaction kinetics, kinome selectivity,
pharmacokinetics, and animal safety. Consistent with these attributes, NuP-4A provides highly potent and safe
correction in disease models. Notably, NuP-4A treatment corrects the basal-epithelial stem cell activation that
drives the key disease phenotypes. This benefit is equivalent to Mapk13-deficiency or combined MAPK13-14
blockade in disease models. Initial toxicology studies suggest that NuP-4A will deliver a satisfactory safety
margin in vivo. and provides a firm basis to move NuP-4A to the next stage of drug development. Smart delivery
using intravenous and inhaled dosing will guide an effective, safe, and practical continuum of care for airway
diseases. Here we concentrate on the next steps in our intravenous dosing program developed in concert with
FDA recommendations. Thus, we propose a STTR Phase II program for NuPeak and Washington University to
advance NuP-4A under the following Specific Aims: Aim 1 will optimize dosing and biomarkers in preclinical
models to refine our clinical trial design; Aim 2 will complete the final non-GLP and GLP pharmacology and
toxicology testing to obtain IND approval; Aim 3 will move our Chemistry, Manufacturing, and Control (CMC)
process into a commercial facility to support clinical trials. The combined Aims will fully prepare the project for
Phase 1 Clinical Trials in humans. NuPeak will operate with the entrepreneurial resources of BioGenerator and
Harrington Discovery Institute and a license from Washington University under a patent for composition and use
of MAPK13 inhibitors, including NuP-4A and back-ups. The commercialization plan is based on completing STTR
Phase II milestones and then performing Phase 1 and then more advanced clinical trials with support from STTR
Phase IIB/III, DOD Clinical Trial Award, Missouri Technology Corporation, and private investors.

Grant Number: 5R42HL149523-03
NIH Institute/Center: NIH
Principal Investigator: Kay Broschat