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

ACS Med Chem Lett. 2019 Oct 17;10(11):1554-1560. doi: 10.1021/acsmedchemlett.9b00334. eCollection 2019 Nov 14.


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.