Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory Diseases

Abstract

Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

“…The rationale for the PI3Kα potency increase is unclear. Erra et al [107] also found that modulations in the affinity pocket could influence selectivity over PI3Kα. Changes to the phenyl substitution pattern greatly affected selectivity ( 20 , 21 , Figure 4d).…”

Identification of Phosphatidylinositol 3-kinase δ (PI3Kδ) Inhibitor: Pharmacophore-based Virtual Screening and Molecular Dynamics Simulation

“…The pharmacophore model was built by employing LigandScout Advanced 4.3 software [14] based on the 3D structure of PI3Kδ-LASW1976 complex, which was retrieved from the Protein Data Bank (www.rcsb.org) with the PDB ID 6G6W [11]. The model was then validated by performing screening against 27 actives taken from BindingDB [15] and 1455 decoys retrieved from the Directory of Useful Decoys-Enhanced (DUD-E) [16].…”

“…Each hit molecule was docked into the active site of PI3Kδ using iDock software [19]. The PI3Kδ structure in complex with LASW1976 was retrieved from the Protein Data Bank (PDB ID: 6G6W) [11]. The receptor was prepared by using AutoDockTools 1.5.6., including adding polar hydrogen and assigning Kollman charges.…”

“…Another PI3K inhibitor, Copanlisib, has been recently approved for the treatment of follicular lymphoma [8][9][10]. Despite those facts, the finding of a new inhibitor of PI3Kδ is urgently needed due to the side effects of the two agents, such as hepatic toxicity, diarrhea, colitis, and intestinal perforation [11]. However, the design of PI3Kδ isoform has not been straightforward due to the similar ATP binding pockets between the isoforms.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–4

“…Despite significant advances in diagnosis and treatment, chronic respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD) remain a major cause of disability and death worldwide [1]. Erra et al report the discovery and the optimization of a series of novel, inhaled, compounds that target the phosphoinositide 3-kinase lipid kinase class I isoform δ (PI3Kδ), primarily involved in the modulation of immune cell function [2,3]. A strategy based on the identification of agents with high potency and selectivity towards PI3Kδ and high plasma clearance led to LAS195319, N -[4-(4-{[(1 S )-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo-[2,1- f ][1,2,4]triazin-2-yl)ethyl]amino}-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)-1 H -indol-6-yl]sulfamide.…”