The CIpP activator, TR-57, is highly effective as a single agent and in combination with venetoclax against CLL cells in vitro

Abstract

Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukemia (CLL) will relapse with drug-resistant disease. The imipridones, ONC-201 and ONC-212, are effective against a range of different cancers, including acute myeloid leukemia (AML) and tumors of the brain, breast, and prostate. These drugs induce cell death through activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR). Here we demonstrate that the novel imipridone analog, TR-57, has efficacy as a single agent and synergises with venetoclax against CLL cells under in vitro conditions that mimic the tumor microenvironment. Changes in protein expression suggest TR-57 activates the UPR, inhibits the AKT and ERK1/2 pathways and induces pro-apoptotic changes in the expression of proteins of the BCL-2 family. The study suggests that TR-57, as a single agent and in combination with venetoclax, may represent an effective treatment option for CLL.

Keywords:

• Chronic lymphocytic leukemia
• tumor microenvironment
• imipridone
• TR-compounds
• ClpP (mitochondrial ATP-dependent Caseinolytic protease P subunit)
• venetoclax

Author contributions

O.G.B., S.Pm, R.I.C., E.J.I., H.L., and D.S.K. designed the study and wrote the manuscript. N.F., Y.S., K.C., O.B., L.T., and O.G.B. generated and analyzed the data.

Disclosure statement

E.J.I. and H.L. have financial interests in Madera Therapeutics, LLC. D.S.K. is a consultant for Madera Therapeutics, LLC. All other authors have no competing interests.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.