BioCentury
ARTICLE | Distillery Therapeutics

Therapeutics: BET bromodomain proteins; bromodomain containing 2 (BRD2); BRD3; BRD4; myeloid-lymphoid or mixed-lineage leukemia (MLL; HRX)

July 16, 2015 7:00 AM UTC

In vitro studies suggest a new class of BET bromodomain protein inhibitors could help treat MLL-mutant leukemias. Chemical synthesis and in vitro testing of tricyclic pyridoindole analogs identified a compound that selectively bound BRD2, BRD3 and BRD4 with Ki values of 3.2-24.7 nM. In human acute leukemia cell lines harboring MLL mutations, the compound inhibited cell growth with IC50 values of 20-66 nM, whereas in an acute leukemia cell line harboring the BCR-ABL tyrosine kinase fusion protein, the compound inhibited growth with an IC50 greater than 2 µM. Next steps could include testing the compound in an animal model of leukemia.

Mitsubishi Tanabe Pharma Corp. and Merck & Co. Inc. have OTX015, a synthetic small molecule inhibitor of BRD2, BRD3 and BRD4, in Phase II testing to treat recurrent glioblastoma multiforme (GBM) and Phase I testing to treat hematologic malignancies...