Cancer

In vitro, cell culture and mouse studies identified two USP10 inhibitors that could help treat AML harboring internal tandem duplication (ITD) mutations in FLT3. Screening of deubiquitinating enzyme (DUB) inhibitors in a cell-based assay of ITD-mutant FLT3 degradation, followed by in vitro testing of hits against a panel of DUBs, identified USP10 as the DUB targeting FLT3 and identified two compounds -- a chlorotetrahydroacridine analog and a thionitrothiophene analog -- that inhibited USP10 with IC₅₀ values of 14 and 6 µM, respectively. In two AML cell lines expressing ITD-mutant FLT3, the compounds decreased FLT3 levels and growth compared with no treatment, whereas in AML cell lines lacking the mutations, the compounds had no effect. In a Rydapt midostaurin-resistant AML cell line expressing ITD-mutant FLT3, the compounds decreased proliferation compared with Rydapt, and in two AML cell lines expressing the mutations, the first compound plus Rydapt or crenolanib besylate synergistically decreased growth compared with any agent alone. In a xenograft mouse model of AML expressing ITD-mutant FLT3, the second compound decreased FLT3 levels in bone marrow cells compared with vehicle. In another mouse model of AML expressing the mutations, the same compound decreased leukemia burden. Next steps could include testing the compounds in additional models of AML.

Novartis AG has Rydapt, an inhibitor of FLT3 and stem cell factor receptor tyrosine kinase (c-Kit; KIT; CD117), approved for AML...