Last update 01 Nov 2024

DHODH x VEGF

Last update 01 Nov 2024

Basic Info

Related Targets

DHODHVEGF

Drugs associated with DHODH x VEGF

PTC-299

Target

DHODH x VEGF

Mechanism

DHODH inhibitors [+1]

Active Org.-

Originator Org.

PTC Therapeutics, Inc.

Active Indication-

Inactive Indication

acute leukemia [+9]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with DHODH x VEGF

NL-OMON50753 / CompletedNot Applicable

An open-label study to investigate the effects of emvododstat on the pharmacokinetics of CYP2D6 and BCRP substrates in healthy volunteers - Emvododstat (PTC299) DDI study with CYP2D6 and BCRP substrates

Start Date05 Oct 2021

Sponsor / Collaborator

PTC Therapeutics, Inc.

NCT04439071 / TerminatedPhase 2/3

Evaluation of the Efficacy and Safety of PTC299 in Hospitalized Subjects With COVID-19 (FITE19)

This is a randomized, double-blind, placebo-controlled, multicenter, 28-day study of adult participants hospitalized with COVID-19, with a safety follow-up telephone call at Day 60.

Start Date09 Jul 2020

Sponsor / Collaborator

PTC Therapeutics, Inc.

NCT03761069 / TerminatedPhase 1

Phase 1B Study of PTC299 in Relapsed/Refractory Acute Leukemias

This is an open-label, non-randomized, Phase 1b study to evaluate the safety, pharmacokinetics (PK) profiles, and preliminary evidence of antitumor activity of PTC299 and the metabolite, O-desmethyl PTC299, in participants with relapsed/refractory acute myeloid leukemia (AML) who have exhausted standard available therapies known to provide clinical benefit. The study is designed as a series of cohort-based dose escalations. For each cohort, a minimum of 3 evaluable participants with PK and safety data will be assessed. Additional participants will be recruited if additional PK data are needed to assess mean exposure based on the observed variability.

Start Date29 Oct 2018

Sponsor / Collaborator

PTC Therapeutics, Inc.

100 Clinical Results associated with DHODH x VEGF

100 Translational Medicine associated with DHODH x VEGF

0 Patents (Medical) associated with DHODH x VEGF

Literatures (Medical) associated with DHODH x VEGF

01 Jan 2021·Virus ResearchQ3 · MEDICINE

The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines

Q3 · MEDICINE

Article

Author: Goodwin, Elizabeth ; Strambio-De-Castillia, Caterina ; Pykett, Mark ; Kong, Ronald ; Naryshkin, Nikolai A ; Wang, Yetao ; O'Keefe, Kylie ; Bavari, Sina ; Cao, Liangxian ; Suder, Ellen L ; Luban, Jeremy ; Trotta, Christopher ; Sattler, Rachel A ; Jacobson, Allan ; Soloveva, Veronica ; Mühlberger, Elke ; Graci, Jason D ; Colacino, Joseph M ; Cintron-Lue, Katherine ; Paessler, Slobodan ; Welch, Ellen M ; Weetall, Marla ; Peltz, Stuart W

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC₅₀ range, 2.0-31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.

01 Jan 2019·Molecular Cancer TherapeuticsQ2 · MEDICINE

Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties

Q2 · MEDICINE

Article

Author: Qi, Hongyan ; Furia, Bansri ; Du, Joshua ; Kong, Ronald ; Hedrick, Jean ; Jacobson, Allan ; Babiak, John ; Branstrom, Art ; Risher, Nicole ; Moon, Young-Choon ; Weetall, Marla ; Colacino, Joseph M. ; Li, Wencheng ; Lennox, William ; Graci, Jason D. ; Cintron, Katherine ; Yeh, Shirley ; Romfo, Charles ; Ma, Jiyuan ; Petruska, Janet ; Trotta, Christopher ; Almstead, Neil G. ; Arasu, Tamil ; Davis, Thomas W. ; Peltz, Stuart W. ; Sheedy, Josephine ; Cao, Liangxian ; Hwang, Seongwoo ; Kim, Min Jung

AbstractPTC299 was identified as an inhibitor of VEGFA mRNA translation in a phenotypic screen and evaluated in the clinic for treatment of solid tumors. To guide precision cancer treatment, we performed extensive biological characterization of the activity of PTC299 and demonstrated that inhibition of VEGF production and cell proliferation by PTC299 is linked to a decrease in uridine nucleotides by targeting dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis. Unlike previously reported DHODH inhibitors that were identified using in vitro enzyme assays, PTC299 is a more potent inhibitor of DHODH in isolated mitochondria suggesting that mitochondrial membrane lipid engagement in the DHODH conformation in situ is required for its optimal activity. PTC299 has broad and potent activity against hematologic cancer cells in preclinical models, reflecting a reduced pyrimidine nucleotide salvage pathway in leukemia cells. Archived serum samples from patients treated with PTC299 demonstrated increased levels of dihydroorotate, the substrate of DHODH, indicating target engagement in patients. PTC299 has advantages over previously reported DHODH inhibitors, including greater potency, good oral bioavailability, and lack of off-target kinase inhibition and myelosuppression, and thus may be useful for the targeted treatment of hematologic malignancies.

01 Feb 2015·Investigative Ophthalmology & Visual ScienceQ2 · MEDICINE

A New Small Molecule For Treating Inflammation and Chorioretinal Neovascularization in Relapsing-Remitting and Chronic Experimental Autoimmune Uveitis

Q2 · MEDICINE

ArticleOA

Author: Leban, Johann ; Wildner, Gerhild ; Diedrichs-Möhring, Maria ; Obermayr, Franz ; Strobl, Stefan

PURPOSEWe investigated the effect of PP-001, a new small molecule inhibitor of dihydro-orotate dehydrogenase in two experimental rat experimental autoimmune uveitis (EAU) models: a spontaneously relapsing-remitting model and a monophasic/chronic disease model that results in late chorioretinal neovascularization. Both of the diseases are induced by immunization with autoantigen peptides.METHODSPrevention was tested using daily oral applications of PP-001 after immunization with the retinal S-antigen peptide PDSAg (for induction of monophasic uveitis and neovascularization) or the interphotoreceptor retinoid-binding protein peptide R14 (for induction of spontaneously relapsing-remitting EAU). Treatment to inhibit relapses and neovascularization was tested using PP-001 daily after the first attack of R14-induced or after onset of PDSAg-induced EAU. Uveitis was graded clinically and histologically. The effect of PP-001 on cytokine secretion and proliferation was evaluated using rat T-cell lines.RESULTSPreventive feeding of PP-001 abrogated both types of EAU. Starting treatment after the resolution of the first attack led to a significant reduction of the number and intensity of relapses in R14-induced EAU. PP-001-treatment initiated after onset or after peak of PDSAg-induced EAU significantly reduced neovascularization (as determined by histology). Proliferation of antigen-specific T-cell lines and secretion of IFN-γ, IL-17, IL-10, IP-10, and VEGF were efficiently suppressed by PP-001.CONCLUSIONSWe investigated a new dihydroorotate dehydrogenase inhibitor as treatment for primary and recurrent disease in relapsing-remitting and chronic rat models of experimental autoimmune uveitis. The small molecule compound PP-001 suppressed proliferation and cytokine secretion of autoreactive T cells (i.e., IFN-g, IL-17, and VEGF) and chorioretinal neovascularization in chronic EAU.

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