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Umbralisib (TGR-1202) is an investigational dual inhibitor of PI3K delta and CK1 epsilon, which is administered orally once daily. The phosphoinositide-3-kinases (PI3Ks) are a family of enzymes involved in many important cellular functions, including cell proliferation and survival, cell differentiation, intracellular trafficking, and immunity. There are 4 isoforms of PI3K (alpha, beta, delta, and gamma), of which the delta isoform is highly expressed in hematopoietic cells. Dysregulation of the PI3K pathway is among one of the most commonly mutated pathways across all of cancer biology.

Umbralisib is highly selective for the delta isoform of PI3K and has limited to no impact on the other isoforms. Umbralisib also inhibits casein kinase 1 epsilon (CK1 epsilon). CK1 epsilon is a major regulator of oncoprotein translation, which drives growth and survival of lymphoma cells, including c-Myc, and may contribute to a protective effect against autoimmune-related toxicities. In addition, umbralisib has a pharmacokinetic (PK) profile that allows for oral, once daily dosing.

Presently, umbralisib is being evaluated in phase 2b and phase 3 trials in patients with NHL and CLL, both as a single agent and in combination with other agents including ublituximab.