IRE1beta Inhibitors: Novel Therapeutics to Manage Excess Mucus in Asthma

PROJECT SUMMARY
Over 25 million Americans have asthma, which places an economic burden on the U.S. of $81.9 billion. Airway
mucus overproduction is a hallmark of asthma, and the quantity and tenacity of mucus are increased during
airway exacerbations. Mucolytics degrade mucus, but do not reduce its production. Although corticosteroids
and other anti-inflammatory therapies indirectly decrease mucus production, and anti-cholinergics inhibit
mucus release from airway epithelia, a significant number of asthmatic continue to suffer from asthma
exacerbations. Clear unmet medical need exists for new therapeutics that directly target airway mucus
overproduction. Airway inflammation and excess mucins activate inositol requiring enzyme 1 (IRE1), a
transmembrane endoplasmic reticulum protein that contains cytoplasmic kinase and RNase domains. IRE1
exists in two isoforms, α and β. IRE1α is ubiquitously expressed, but IRE1β is only expressed in mucous cells
of the respiratory and GI tracts. Key residues in the kinase ligand binding pocket differ for the two isozymes.
Activation of IRE1β (but not IRE1α) kinase and RNase is required for airway mucin production. IRE1β (but not
IRE1α) expression is up-regulated in asthmatic human bronchial epithelia (HBE), providing an amplifying
mechanism for airway exacerbations due to mucus overproduction. Irex Pharma has developed novel IRE1β-
specific assays to support a full synthetic medicinal chemistry campaign to identify potent, selective and
efficacious IRE1β inhibitors to treat airway mucus overproduction. Our focused testing of IRE1 ligands
revealed a distinct mechanism for blocking IRE1β-dependent mucin production. Most IRE1 kinase inhibitors
tested activate the IRE1 RNase. We identified an IRE1β ligand that blocks both kinase and RNase activities
and mucin production in HBE, providing proof-of-concept that a small molecule IRE1β ligand with this profile
can block mucus overproduction in human airways. Aim 1 proposes to use structure-based design to guide the
synthesis of novel analogs based on our current hits. Structure-activity relationships will be established using
an iterative approach. Our goal is to identify nontoxic, patentable, nanomolar compound(s) using our teamandapos;s
extensive knowledge of kinase inhibitor design, computational chemistry, synthetic chemistry, and novel IRE1
assays. Aim 2 proposes to test our IRE1β inhibitors with favorable profiles for ability to reduce 1) interleukin-13
(IL-13)-stimulated MUC5AC production in HBE cultures and 2) house dust mite (HDM; an in vivo stimulus
relevant to asthma)-induced airway mucin overproduction and hyper-responsiveness in mice. PK, early
ADMET and kinase selectivity will be obtained for top compounds. Our goal is to identify a patentable IRE1β
inhibitor able to reduce IL-13-increased MUC5AC in HBE and able to lower HDM-induced MUC5AC production
and hyper-responsiveness in mouse airways with favorable potency, selectivity, toxicity and developability
profiles. Completion of these studies will lay the groundwork for Phase II development of IRE1β antagonists as
novel therapeutics for asthma.PROJECT NARRATIVE.
A cardinal feature of asthma is the overproduction of mucins that leads to airway mucus obstruction associated
with increased morbidity. We will develop inhibitors of IRE1β, a key protein discovered by our group to be
required for airway mucin production. Our studies are expected to lead to novel asthma therapeutics.