BioCentury
ARTICLE | Distillery Therapeutics

Cancer

July 10, 2018 9:35 PM UTC

In vitro, cell culture and mouse studies identified an aminopyrimidine-based dual MAPK1/MAPK3 inhibitor that could help treat BRAF-mutant melanoma and colorectal cancer. Fragment-based screening, chemical synthesis and in vitro enzyme activity assays of aminopyrimidine analogs yielded a compound that produced 60% inhibition of MAPK3 and 50% inhibition of MAPK1 at concentrations of 1 and 3 nM, respectively. In human BRAF-mutant melanoma and colorectal adenocarcinoma cell lines, the compound inhibited proliferation with IC50 values of 4.9 and 7.5 nM, respectively, and in the melanoma cell line, the compound inhibited phosphorylation of MAPK with an IC50 of 2.3 nM. In a xenograft mouse model of BRAF-mutant colorectal cancer, the compound decreased tumor growth compared with vehicle. Next steps could include testing the compound in mouse models of BRAF-mutant melanoma.

BioMed Valley Discoveries Inc. has ulixertinib, a inhibitor of MAPK1 and MAPK3, in Phase I/II testing to treat advanced solid tumors and Phase I testing to treat pancreatic cancer...