Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors

Abstract

The predominant expression of phosphoinositide 3-kinase δ (PI3Kδ) in leukocytes and its critical role in B and T cell functions led to the hypothesis that selective inhibitors of this isoform would have potential as therapeutics for the treatment of allergic and inflammatory disease. Targeting specifically PI3Kδ should avoid potential side effects associated with the ubiquitously expressed PI3Kα and β isoforms. We disclose how morphing the heterocyclic core of previously discovered 4,6-diaryl quinazolines to a significantly less lipophilic 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, followed by replacement of one of the phenyl groups with a pyrrolidine-3-amine, led to a compound series with an optimal on-target profile and good ADME properties. A final lipophilicity adjustment led to the discovery of CDZ173 (leniolisib), a potent PI3Kδ selective inhibitor with suitable properties and efficacy for clinical development as an anti-inflammatory therapeutic. In vitro, CDZ173 inhibits a large spectrum of immune cell functions, as demonstrated in B and T cells, neutrophils, monocytes, basophils, plasmocytoid dendritic cells, and mast cells. In vivo, CDZ173 inhibits B cell activation in rats and monkeys in a concentration- and time-dependent manner. After prophylactic or therapeutic dosing, CDZ173 potently inhibited antigen-specific antibody production and reduced disease symptoms in a rat collagen-induced arthritis model. Structurally, CDZ173 differs significantly from the first generation of PI3Kδ and PI3Kγδ-selective clinical compounds. Therefore, CDZ173 could differentiate by a more favorable safety profile. CDZ173 is currently in clinical studies in patients suffering from primary Sjögren's syndrome and in APDS/PASLI, a disease caused by gain-of-function mutations of PI3Kδ.

Keywords: B cell inhibition; PI3Kδ inhibitor; PK/PD studies; Phosphoinositide-3-kinase delta inhibitor; lead optimization; structure−activity relationship.

Figure 1

(Left) Structural alignment of PI3Kα and PI3Kδ with compound 1a bound to the ATP sites. The protein part of PI3Kδ/compound 1a (PDB 5IS5) is depicted as a gray surface. Amino acid side chains T750, M752, W760, and the inhibitor are represented as blue sticks for PI3Kδ. The corresponding amino acid and inhibitor structures in PI3Kα (PDB 5ITD) are shown in yellow. (Right) Comparison of the binding modes of CDZ173 (green sticks) and compound 1a (blue sticks) to the active site of PI3Kδ (gray surface with amino acids T750, M752, and W760 colored in red, yellow, and magenta, respectively.

Figure 2

Dose-dependent inhibition of SRBC-specific IgM response by CDZ173 (error bars indicate SD); ***p < 0.001 compared to vehicle (student’s t test, two-tailed distribution).

Figure 3

Inhibition of paw swelling in a therapeutic rat CIA experiment (dosing after disease onset, error bars indicate SEM). Antigen priming (I°) and boost (2°) indicated with arrows. Treatment period indicated with horizontal line at bottom of graph. *p < 0.01.