Background

DHODH is a rate-limiting enzyme in de novo pyrimidine synthesis. Rapidly dividing cancer cells are therefore sensitive to blockade of this pathway. New research has shown DHODH inhibition can induce differentiation in acute myeloid leukemia (AML) cell lines, translating to increased survival in animal models. There is also evidence that DHODH inhibitors can produce cytotoxic effects through p53 upregulation and mitochondrial effects in primary AML blasts.

AML affects more than 21,000 people annually in the United States. The prevalence of AML in this country is estimated to be over 60,000 people. Hematopoietic stem cell transplantation is still the most successful therapy; however, the five-year survival remains less than 30%. Patients ineligible for stem cell transplant have < 10% cure rate.

Technology Overview

Recent research has demonstrated the potential to treat hematologic malignancies through inhibition of dihydroorotate dehydrogenase (DHODH). The Ohio State University, in collaboration with Hendrix College, is developing DHODH inhibitors (DHODHi) for the treatment of hematological malignancies, including acute myeloid leukemia (AML), multiple myeloma (MM), and acute Graft vs. Host Disease (aGVHD). Importantly, OSU is investigating rational therapeutic combination strategies based on its discovery of DHODHi-mediated upregulation of additional druggable targets having clinically approved targeted therapeutics.

Stage of Development: Lead optimization

Known Characteristics of Lead Compound 41:

• Biochemical IC50 of 0.90 nM
• Dose linear oral bioavailability in mice
• Clean kinome screen
• Favorable in vitro ADME and PK
• Superior single-agent in vivo efficacy compared to BAY2402234 and Aslan003 in disseminated AML MOLM-13 xenograft model
• Superior in vivo efficacy in combination with decitabine in disseminated HL-60 AML xenograft model
• 60% tumor-free survival in H929 multiple myeloma xenograft model when combined with an approved targeted therapeutic
  • DHODH inhibition upregulates an alternative druggable target
• Signifcant survival advantage in xenogeneic aGVHD model
  • Retains graft vs. leukemia effect

Next Steps:

• Rat and Dog PK of Compound 41
• Pilot toxicity and dose range finding of Compound 41
• Continued lead optimization to identify back-up compounds

Competitive Advantages

• More potent than Brequinar (Clear Creek Bio) and PTC-299 (PTC Therapeutics)
• Short, 3-step synthesis of lead compound
• Strong patent portfolio including issued patents claiming lead compounds, methods of use, and novel combination therapy strategies