BioCentury
ARTICLE | Distillery Therapeutics

Cancer

June 7, 2017 4:04 PM UTC

Cell culture and mouse studies identified an aminoquinoline-based dual DNMT1/EHMT2 inhibitor that could help treat ALL, AML and diffuse large B cell lymphoma (DLBCL). Chemical synthesis and in vitro testing of 4-aminoquinoline analogs, followed by optimization of hits, yielded a compound that inhibited DMNT1 and EHMT2 with IC50 values of 8 and 382 nM, respectively. In ALL, AML and DLBCL cell lines, the compound increased apoptosis and decreased proliferation and cell cycle progression compared with monotherapy with ENMT2 inhibitor tool compounds or the DNA methyltransferase inhibitors Vidaza azacitidine and Dacogen decitabine. In xenograft mouse models of ALL and AML, the compound increased survival compared with vehicle. Next steps could include testing the dual DNMT1/EHMT2 inhibitor in models of DLBCL.

Otsuka Pharmaceutical Co. Ltd., Eisai Co. Ltd. and Johnson & Johnson market Dacogen for Myelodysplastic syndrome (MDS) and have it approved for AML and in Phase I testing for ovarian cancer...