Discovery of Narrow Spectrum Kinase Inhibitors: New Therapeutic Agents for the Treatment of COPD and Steroid-Resistant Asthma

Abstract

The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery.

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…Several drugs that inhibit Hck, including PP2 and dasatinib, are available, and new drugs are in development (Poh et al, 2015). Inhaled drugs that have inhibitory effects on Hck are also in clinical development for the treatment of severe asthma and COPD (Norman, 2014a;Onions et al, 2016).…”

“…There is a case for the development of inhaled multikinase inhibitors for severe airway disease. Several narrow spectrum kinase inhibitors suitable for inhaled delivery have been developed for the treatment of corticosteroid-resistant inflammation in severe asthma and COPD (Onions et al, 2016). These drugs inhibit p38a, p38g and Hck and are more effective than p38a inhibitors in suppressing the release of inflammatory cytokines from macrophages in vitro and in treating inflammation in mice exposed to cigarette smoke, which is resistant to corticosteroids.…”

“…Loss of effect of kinase incubators is also seen in the treatment of chronic inflammatory disease, such as rheumatoid arthritis and inflammatory bowel disease, and tends to develop over several weeks of treatment (Barouch-Bentov and Sauer, 2011). This may arise as compensatory pathways are upregulated to circumvent the pathway blocked by the kinase inhibitor and may be overcome by also blocking the compensatory pathway, for example with narrow spectrum kinase inhibitors (Onions et al, 2016).…”

“…It has so far proven difficult to develop such drugs, but inhaled p38 MAPK inhibitors are currently in clinical development for severe asthma and COPD (Millan, 2011;Norman, 2015). Inhaled PI3Kg/d inhibitors are also in development for severe asthma and COPD because they may overcome the corticosteroids resistance in these diseases (Norman, 2014a;Onions et al, 2016).…”

Superior anti-inflammatory effects of narrow-spectrum kinase inhibitors in airway smooth muscle cells from subjects with chronic obstructive pulmonary disease

“…[1][2][3] Cytokines are regulated by various protein kinases that have in part redundant functions. 4,5 Narrow-spectrum protein kinase inhibitors (NSKIs) are novel anti-inflammatory agents targeting p38MAPK and Src (RV568) or p38MAPK, Src, and Syk (RV1088). 4,5 To be superior to current and prospective COPD treatment options, NSKIs should (1) reduce the expression of corticosteroid-resistant cytokines such as CXCL8, (2) reduce the expression of corticosteroid-sensitive cytokines such as GM-CSF with equal or better efficacy than do corticosteroids such as fluticasone propionate (FP), which is frequently used in COPD therapy, 6 and (3) reduce the expression of inflammatory cytokines more efficiently than do single kinase inhibitors (SKIs), particularly pan-p38MAPK inhibitors such as BIRB796 that are in development for COPD.…”