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Targeted molecules for the treatment of cancer

College
College of Medicine (COM)
Researchers
Byrd, John
Abdulrahim, Mouad
Elgamal, Ola
Goodwin, Thomas
Hertlein, Erin
Ravikumar, Pratheepa
Shah, Dimple
Licensing Manager
Ezzell, Janel
(614) 292-5253
ezzell.11@osu.edu

T2018-003 Novel dihdroorotate dehydrogenase (DHODH) small-molecule inhibitors for the treatment of Acute Myeloid Leukemia.

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.

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 for the treatment of hematological malignancies, including acute myeloid leukemia (AML).

Stage of Development: Lead optimization

Known Characteristics of Compound 1:

  • Biochemical IC50 of 43 nM
  • Dose linear oral bioavailability in mice
  • Clean kinome screen
  • In vitro ADME (no major concerns)

Next Steps:

  • Efficacy of Compound 1 in PDX
  • Rat and Dog PK of Compound 1
  • Pilot toxicity of Compound 1
  • Evaluate follow-on compounds

Benefits

  • More potent than Brequinar in AML cell lines (Brequinar is in early clinical trials for AML.)
  • Differential growth inhibition compared to Brequinar in murine AML models with defined genetic phenotype