SUMMARY:
Researchers from UCLA’s Department of Molecular and Medicinal Pharmacology have discovered two protein kinase inhibitors that effectively inhibit dihydroorotate dehydrogenase, an enzyme linked to cancer progression.
BACKGROUND:
During the progression of cancer, normal healthy cells undergo mutation that converts normal cell phenotypes and functions to aberrant ones. One category of transformation is characterized by an altered metabolism that allows cancer cells to sustain higher proliferative rates and resist cell death signals, called metabolic reprogramming. Cancer therapy has long relied on targeting the aberrant metabolism observed in tumors, however, with limited degrees of efficacy. Many prospective metabolic drug targets in cancer are not active uniquely in cancer cells, making drugging them difficult without toxic side-effects. One pathway of great interest to the development of new cancer therapies, pyrimidine nucleotide metabolism, is an attractive target because of its specificity to cancer progression. Furthermore, rate-limiting enzymes in pyrimidine biosynthesis have been directly linked to mutant KRAS and MYC, two frequently mutated proteins in cancers. In particular, dihydroorotate dehydrogenase (DHODH), an enzyme specific to the de novo pyrimidine biosynthesis pathway, has been shown to be critical for melanoma progression. Development of therapies targeting DHODH could therefore have great potential value in treating cancer.
INNOVATION:
UCLA researchers in the Department of Molecular and Medicinal Pharmacology have identified that two clinically established PDK-1 inhibitors also inhibit DHODH. Of the protein kinase inhibitors evaluated in an in-house-designed differential metabolic modifier screen, OSU-03012 and TAK-632 scored the highest and second-highest, respectively, against the pyrimidine de novo pathway (DNP). 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 (pan-RAF) are relevant for cancer therapy, as is the newly-identified target (DHODH). Additionally, DHODH is also a target for therapies against microbes in antibacterial, antiviral, and antifungal settings. Taken together, OSU-03012 and TAK-632 hold great promise for treating a wide range of diseases and are thus uniquely positioned for further therapeutic evaluation.
POTENTIAL APPLICATIONS:
● Novel therapeutic strategy in treating many types of cancer
● Antiviral agent against a host of diseases associated with DHODH, including Ebola, Zika, Influenza, and Epstein Barr
● Therapeutic intervention in antibacterial and antifungal settings
ADVANTAGES:
● Compounds identified have multiple targets (PDK-1 for OSU-03012 and pan-RAF for TAK-632) associated with cancer cells, giving them greater potency as cancer therapies
● Low IC50 values indicate highly potent and selective inhibitory effects on the pyrimidine de novo pathway
● OSU-03012 has already received Orphan Drug Status in Europe
DEVELOPMENT-TO-DATE:
Researchers have successfully demonstrated the efficacy of OSU-03012 and TAK-632 in inhibiting DHODH in a dose-dependent manner in vitro and confirmed the formation of protein-ligand complexes structurally using crystallography.
Related Papers (from the inventors only):
Abt ER, Rosser EW, Durst MA, et al. Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism. Cell Chem Biol. 2020;27(2):197-205.e6. doi:10.1016/j.chembiol.2019.10.012