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Protein Kinase Inhibitors Which Also Target Dihydroorotate Dehydrogenase
University of California - Los Angeles
Small molecule
Oncology
Hit To Lead or Lead Optimization
• UCLA inventors have identified that two clinically established PDK-1 inhibitors also inhibit DHODH. Each had sub-micromolar IC50 values against a pancreatic cancer cell line starved of uridine and forced to rely upon DNP, indicating highly potent and selective inhibitory effects.
• The DHODH inhibitory action of these compounds was subsequently confirmed through use of a colorimetric assay using purified recombinant human DHODH, which demonstrated that both compounds inhibited the enzyme in a dose-dependent manner.
• Co-crystal structures of each compound complexed with human DHODH were also obtained, unambiguously confirming their DHODH-inhibitory ability. The intended targets of OSU-03012 (PDK-1) and TAK-632 (panRAF) are relevant for cancer therapy, as is the newly-identified target (DHODH).
WO2020232445A1
Metabolic modifier screen reveals secondary targets of protein kinase inhibitors within nucleotide metabolism, Cell Chem Biol. (2020)
