PI3Kδ belongs to the class I Phosphoinositide 3-kinases (PI3Ks). PI3Kδ plays a critical role in chronic obstructive pulmonary disease (COPD). IHMT-PI3Kδ-372 is a potent and selective PI3Kδ inhibitor for the treatment of COPD. In the biochemical assay, IHMT-PI3Kδ-372 inhibits PI3Kδ (IC50=14 nM) with high selectivity over other class I PI3Ks (56∼83 fold). IHMT-PI3Kδ-372 also achieves good selectivity over other protein kinases.

In the cell, IHMT-PI3Kδ-372 selectively and potently inhibits the PI3Kδ-mediated phosphorylation of AKT T308. However, IHMT-PI3Kδ-372 does not inhibit other class I PI3K-mediated signaling. Besides strong binding to PI3Kδ, IHMT-PI3Kδ-372 also displays binding to PI3Kβ, γ, and PI4Kβ in the PIK family as well as Chk2 kinase. IHMT-PI3Kδ-372 shows moderate inhibition of CYP2C9 (IC50=2.7 μM) and no apparent inhibition against CYP1A2, CYP2B6, CYP2C19, and CYP3A4 (IC50s >10 μM). In addition, IHMT-PI3Kδ-372 decreases the inflammatory cell infiltration in a dose-dependent manner.

In vivo, IHMT-PI3Kδ-372 improves lung function in a rodent model of pulmonary inflammation. Furthermore, IHMT-PI3Kδ-372 is suitable for inhaled delivery. In rats, inhalation of 5 mg/kg dose of IHMT-PI3Kδ-372 displays a half-life of 2.3 h, low exposure of 66 ng/mL, and high clearance of 348.5 mL/min/kg in plasma but high exposure of 5599 ng/g (6 h after inhalation) in lung tissue. IHMT-PI3Kδ-372 is stable in human, rat, and mouse liver microsomes. However, IHMT-PI3Kδ-372 has moderate stability in monkey and dog liver microsomes.

Overall, IHMT-PI3Kδ-372 improves lung function and reduces the inflammatory patterns characteristic of COPD. These results suggest that IHMT-PI3Kδ-372 might be a new potential therapeutic candidate for COPD.

Feng Li, et al. J Med Chem. 2020 Nov 25;63(22):13973-13993.