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.
Eddy W Yue  1 ,  Yun-Long Li  1 ,  Brent Douty  1 ,  Chunhong He  1 ,  Song Mei  1 ,  Brian Wayland  1 ,  Thomas Maduskuie  1 ,  Nikoo Falahatpisheh  1 ,  Richard B Sparks  1 ,  Padmaja Polam  1 ,  Wenyu Zhu  1 ,  Joseph Glenn  1 ,  Hao Feng  1 ,  Ke Zhang  1 ,  Yanlong Li  1 ,  Xin He  1 ,  Kamna Katiyar  1 ,  Maryanne Covington  1 ,  Patricia Feldman  1 ,  Niu Shin  1 ,  Kathy He Wang  1 ,  Sharon Diamond  1 ,  Yu Li  1 ,  Holly K Koblish  1 ,  Leslie Hall  1 ,  Peggy Scherle  1 ,  Swamy Yeleswaram  1 ,  Chu-Biao Xue  1 ,  Brian Metcalf  1 ,  Andrew P Combs  1 ,  Wenqing Yao  1
Affiliations
  • 1. Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
PMID: 31749910 DOI: 10.1021/acsmedchemlett.9b00334
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.

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