Phosphoinositide 3-kinases (PI3Ks), are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. Class I PI3K enzymes consist of four distinct catalytic isoforms, PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ. Among them, PI3Kδ is the main isozyme responsible for the activation of the PI3K pathway in B-cell biology, functioning as a downstream mediator of the B-cell receptor (BCR), Toll-like receptors, and cytokine receptors. When dysregulated, PI3Kδ can lead to the development of hematologic malignancies including acute myeloid leukemia and chronic lymphocytic leukemia. As such, there are currently intense efforts toward identifying inhibitors of PI3Kδ to treat hematologic malignancies as well as other cancers and immunologic diseases.
Parsaclisib (also known as INCB050465 or IBI-376) is a potent, selective and orally active PI3Kδ inhibitor.
Meanwhile, Parsaclisib shows approximately 20,000-fold selectivity for PI3Kα, PI3Kβ, PI3Kγ and 57 other kinases. Parsaclisib directly blocks PI3K signaling-mediated cell proliferation in B-cell lines. Moreover, Parsaclisib indirectly controls tumor growth by lessening immunosuppression through regulatory T-cell inhibition in a syngeneic lymphoma model. However, diffuse large B-cell lymphoma cell lines overexpressing MYC are insensitive to Parsaclisib, but their proliferative activities are reduced by suppression of MYC gene transcription. In vivo, Parsaclisib (10 mg/kg) inhibits tumor growth in the BALB/c mice bearing the A20 murine lymphoma cells. In additional, Parsaclisib (0.1-10 mg/kg) slows Pfeiffer xenograft tumor growth in a dose-dependent manner. Thus, Parsaclisib has the potential for the research of relapsed or refractory B-cell malignancies.
To sum up, Parsaclisib is a potent, selective and orally active PI3Kδ inhibitor with anticancer effcts.
References:
[1] Niu Shin, et al. J Pharmacol Exp Ther. 2020 Jul;374(1):211-222.
[2] Cancer Res (2015) 75 (15_Supplement): 2671.