Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta (PI3Kδ) and Casein kinase I isoform epsilon (CK1ε) (PI3Kδ / CK1ε)

The dual target PI3Kδ / CK1ε consists of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta (PI3Kδ) and Casein kinase I isoform epsilon (CK1ε) [1, 12]. PI3Kδ is a lipid kinase primarily expressed in leukocytes, where it plays a vital role in B-cell receptor signaling, development, and survival [9, 17]. CK1ε is a serine/threonine kinase that regulates diverse processes, including the circadian rhythm, Wnt/β-catenin signaling, and the translation of oncogenic proteins like c-Myc and BCL2 [3, 16]. This dual-targeting strategy, exemplified by the drug umbralisib, aims to achieve synergistic anti-tumor activity in hematological malignancies while potentially mitigating the immune-mediated toxicities common to selective PI3Kδ inhibitors [1, 4]. Specifically, CK1ε inhibition is hypothesized to preserve the function of regulatory T cells (Tregs), thereby reducing the incidence of autoimmune-like side effects such as colitis [1, 12]. However, clinical safety concerns, including an increased risk of death, led to the withdrawal of the primary dual inhibitor from the market in 2022 [6, 10]. Despite these challenges, the target remains a significant area of research for its unique immunomodulatory properties and its ability to disrupt multiple survival pathways in malignant cells [12, 14].

Other names

p110δPIK3CDPhosphoinositide 3-kinase deltaPhosphatidylinositol 3-kinase catalytic subunit deltaCSNK1ECasein kinase 1 epsilonCasein kinase I isoform epsilonHCKIE

Dual inhibition of PI3Kδ and CK1ε, which disrupts the PI3K/AKT/mTOR signaling pathway in B-cells and downregulates the translation of oncogenic proteins such as c-Myc and BCL2 while preserving regulatory T cell function.