BioCentury
ARTICLE | Distillery Therapeutics

Therapeutics: Isocitrate dehydrogenase 1 (IDH1)

November 19, 2015 8:00 AM UTC

In vitro and mouse studies identified an inhibitor of mutant IDH1 that could help treat AML. Screening of a library of small molecules for binding to a heterodimer of mutant and wild-type IDH1, followed by optimization and in vitro testing of hits, identified a tetrahydropyrazolopyridine-based compound that inhibited multiple IDH1 mutants with IC50 values of 2.9-4.6 nM and wild-type IDH1 with an IC50 of 46 nM. In a mouse xenograft model of IDH1-mutant AML, an analog of the compound with optimized PK properties increased myeloid differentiation of AML cells and decreased the fraction of cells with a leukemic blast phenotype compared with vehicle. Next steps could include safety and toxicity testing of the PK-optimized compound.

Novartis AG has IDH305, an IDH1 inhibitor, in Phase I testing for cancer...