Umbralisib (TGR1202; RP-5264)

Description: Umbralisib (formerly also known as TGR-1202; RP5264) is a novel, highly specific, orally bioavailable and potent PI3Kdelta inhibitor with antineoplastic activity. It inhibits PI3Kdelta with IC50 and EC50 of 22.2 nM and 24.3 nM, respectively; In addition, Umbralisib is also active against CK1epsilon with an EC50 value of 6.0 uM. TGR-1202, but not the approved PI3Kdelta inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells. TGR-1202 and carfilzomib (TC) synergistically inhibited phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), leading to suppression of c-Myc translation and silencing of c-Myc-dependent transcription. The synergistic cytotoxicity of TC was rescued by overexpression of eIF4E or c-Myc. TGR-1202, but not other PI3Kdelta inhibitors, inhibited casein kinase-1 epsilon (CK1epsilon). Targeting CK1epsilon using a selective chemical inhibitor or short hairpin RNA complements the effects of idelalisib, as a single agent or in combination with carfilzomib, in repressing phosphorylation of 4E-BP1 and the protein level of c-Myc. These results suggest that TGR-1202 is a dual PI3Kdelta/CK1epsilon inhibitor, which may in part explain the clinical activity of TGR-1202 in aggressive lymphoma not found with idelalisib. Targeting CK1epsilon should become an integral part of therapeutic strategies targeting translation of oncogenes such as c-Myc.

References: Blood. 2017 Jan 5; 129(1):88-99; Swaroop Vakkalanka, et al. AACR Poster. 2012, Poster3741.

Related CAS #: 1532533-78-0 (HCl); 1532533-69-9 (Umbralisib R-enantiomer); 1532533-67-7 (free base); 1532533-75-7 (sulfate);