Umbralisib hydrochloride (TGR-1202 hydrochloride) is a novel PI3Kδ inhibitor, with IC50 and EC50 of 22.2 nM and 24.3 nM, respectively; Umbralisib hydrochloride (TGR-1202 hydrochloride) is also active against CK1ε, with an EC50 value of 6.0 μM. PI3Kδ|22.2 nM (IC50)

Umbralisib (RP5264) causes a half-maximal inhibition of human whole blood CD19 cell proliferation between 100-300 nM[1]. In human lymphoma and leukemia cell lines, Umbralisib (TGR-1202; 10 nM-100 μM) inhibits phosphorylated AKT at Ser473 in a concentration-dependent manner. Umbralisib and carfilzomib synergistically kill blood cancer cells through disrupting the 4E-BP1-eIF4F-c-Myc axis. Umbralisib and carfilzomib in combination synergistically and selectively silence the c-Myc and E2F transcription programs. Umbralisib (15-50 μM) potently represses the expression of c-Myc in the DLBCL cell line LY7, and is uniquely characterized with structural features suitable for targeting CK1ε in lymphoma cells[2].

In a subcutaneous xenograft model of T-cell acute lymphoblastic leukemia (T-ALL) in NOD/SCID mice using the MOLT-4 cell line, Umbralisib (TGR-1202; 150 mg/kg, daily p.o.) significantly shrinks the tumors by day 25[2].

[1]. Swaroop Vakkalankaa, et al. Inhibition of PI3Kδ kinase by a selective, small molecule inhibitor suppresses B-cell proliferation and leukemic cell growth. [2]. Deng C, et al. Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies. Blood. 2017 Jan 5;129(1):88-99