AI-10-49

AI-10-49 is a selective inhibitor of CBFβ –SMMHC and RUNX1 interaction with a FRET IC50 value of 260nM.
AI-10-49 restores RUNX1 transcriptional activity, displays favorable pharmacokinetics, and delays leukemia progression in mice. Treatment of primary inv(16) AML patient with AI-10-49 triggers selective cell death. Direct inhibition of the oncogenic CBFβ-SMMHC fusion protein may be an effective therapeutic approach for inv(16) AML, and they provide support for transcription factor targeted therapy in other cancers. The stability of RUNX1, CBFb, and CBFb-SMMHC was not affected by AI-10-49 [1].
In 11 human leukemia cell lines, ME-1 cells were the only cell line highly sensitive to AI-10-49. In ME-1 cell, AI-10-49 has enhanced inhibitory activity on growth (IC50 = 0.6 mM) compared with the parent protonated bivalent compound AI-4-83 (IC50 of ~3 mM). In normal human bone marrow cells, AI-10-49 showed negligible activity (IC50 > 25 mM), which indicated a robust potential therapeutic window. In chromatin-immunoprecipitation (ChIP) assays, treatment of ME-1 cells for 6 hours with AI-10-49 increased RUNX1 occupancy 8-, 2.2-, and 8-fold at the RUNX3, CSF1R, and CEBPA promoters, respectively.
After treatment with AI-10-49 to leukemia mice significantly prolonged their lives, and after 7 days of administration of AI-10-49, we observe no evidence of toxicity [1].
Reference:
1.Illendula A, Pulikkan JA, Zong H et al. A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice. Science. 2015 Feb 13;347(6223):779-784.