INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of Phosphoinositide 3-Kinase Delta (PI3Kδ)

Abstract

A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδ inhibitors, such as idelalisib (1), duvelisib (2), and INCB040093 (3, dezapelisib). Parsaclisib (20) is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.

Figure 1

Structures of idelalisib (1), duvelisib (2), INCB040093 (3, dezapelisib), and INCB050465 (20, parsaclisib).

Figure 2

Design of quinoline and cinnoline inhibitors 4–6.

Figure 3

Monocyclic purine inhibitors 7–11.

Figure 4

Evolution of purine inhibitor 11 to aminocyanopyrimidine inhibitors 12 and 13 to pyrazolopyrimidine inhibitors 14 and 15.

Figure 5

Monocyclic pyrazolopyrimidine inhibitors 16–18 with 3-substituted saturated cyclic rings.

Figure 6

Proposed binding model of 20 (orange) with PI3Kδ overlaid with 3 (cyan).

Figure 7

(A) Compound 20 suppresses tumor growth in the Pfeiffer mouse xenograft model. Compound 20 was administered orally twice daily for 14 days. The percentage of tumor growth inhibition (TGI) was measured on the final day of study. (B) Analysis of mice from the Pfeiffer xenograft model revealed inhibition of the phosphorylation of AKT at Ser473.