Immunomodulating Agents in Gastrointestinal Disease
Thomas F. Kresina in Immune Modulating Agents, 2020
Brequinar sodium is an investigational agent that has not yet received FDA approval. Initial phase I and phase II trials in renal transplantation recipients suggested the drug was well tolerated and reduced the incidence of steroid-refractory rejection if substituted for azathioprine in a “triple therapy” immunosuppressive regimen [192], However, further multicenter study suggested that it has a narrow therapeutic index, and that there was no clear reduction in rejection episodes [190]. In theory, synergistic use of Brequinar with CSA offers the potential advantage of potent T and B cell inhibition; however, further clinical studies are needed to determine this agent’s role in immunosuppressive regimens.
An expert overview of emerging therapies for acute myeloid leukemia: novel small molecules targeting apoptosis, p53, transcriptional regulation and metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Kapil Saxena, Marina Konopleva
Given that DHODH is necessary for pyrimidine biosynthesis, it has been evaluated as a cancer target since at least the late 1980s with the development of the DHODH inhibitor brequinar [130]. Though brequinar showed activity in preclinical models of solid tumors, it failed to demonstrate significant efficacy in clinical trials for various solid tumors (breast, lung, ovarian, melanoma, colon), had a narrow therapeutic window, and was thus largely abandoned as a chemotherapeutic agent [129,130,132]. Other DHODH inhibitors, such as leflunomide and its active metabolite teriflunomide, did attain FDA approval. However, their use has been largely limited to the treatment of patients with autoimmune diseases (rheumatoid arthritis, multiple sclerosis), and no DHODH inhibitor is currently FDA approved for the treatment of cancer [130]. Thus, the recent finding that DHODH inhibitors could induce myeloblast differentiation provided a resurgence in the study of DHODH inhibitors for cancer treatment. Using brequinar, it was demonstrated that DHODH inhibition could induce myeloid differentiation and prolong survival of mice in xenograft models of human AML [124].
The emergence of dihydroorotate dehydrogenase (DHODH) as a therapeutic target in acute myeloid leukemia
Published in Expert Opinion on Therapeutic Targets, 2018
David B. Sykes
The DHODH inhibitor brequinar (NSC 368,390, DuP-785) demonstrated potent in vitro and in vivo anti-tumor activity across multiple tumor models [3]. Brequinar was quickly advanced to phase I clinical trials in patients with advanced solid tumor malignancies [4–6]. While brequinar was generally well-tolerated, and demonstrated occasional durable responses, the clinical experience was disappointing across more than a dozen trials encompassing more than 500 patients [7–11].
Related Knowledge Centers
- Antiviral Drug
- Cell Potency
- Dihydroorotate Dehydrogenase
- Immunosuppressive Drug
- Nucleotide
- Pyrimidine
- Methotrexate
- Organ Transplantation
- Antiparasitic
- Leflunomide