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Dihydroorotate dehydrogenase inhibitors as broad spectrum antiviral and antitumor agents

Country of origin:
Country: 
GERMANY
Opportunity:
External Id: 
TODE20200304002
Published
04/03/2020
Last update
02/04/2020
Expiration date
03/04/2021

Keywords

Partner keyword: 
Clinical Research, Trials
Medical Research
Pharmaceutical Products / Drugs
Oncology
Other clinical medicine
Pharmaceuticals/fine chemicals
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Summary

Summary: 
A German university developed easy-to-synthesize dihydroorotate dehydrogenase (DHODH) inhibitors with high metabolic stability and selectivity to inhibit growth of fast proliferating cells, e.g. of tumors or virally infected cells. Transfer of rights, license agreements or R&D cooperation are offered to industrial partners with a focus on the development and commercialization of chemotherapeutics, virostatics, or antitumoral drugs.

Description

Description: 

Fast proliferating cells, like tumor cells, or virally infected cells are highly dependent on de novo nucleotide synthesis. An inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) downregulates de novo pyrimidine nucleotide synthesis and thus limits cell growth and proliferation of fast proliferating cells. Hence, DHODH inhibitors could be excellent therapeutic in fields such as viral infections, immunosuppression or cancer treatment. Still, DHODH inhibitors have not yet been employed due to several shortcomings, e.g. minor inhibitory effect, unacceptable side-effects, toxicity or inconsistent pharmacokinetics.

A research group at a German university has developed novel DHODH inhibitors, which overcome these limitations and show a broad antiviral activity. This is achieved by suppressing the de novo synthesis of uridine monophosphate (UMP) based pyrimidine nucleotides, leading to limitations in cell growth and proliferation, especially for fast proliferation cells including tumor cells or virally infected cells, whereas the host cell’s demand for nucleotides is covered by the salvage pathway for resting cells.

The new DHODH inhibitors can be obtained in multi-gram scale via short synthetic routes. They show high antiviral activity down to the low nanomolar range in simian, mouse, hamster and human cell lines against several RNA virus families including bunya, flavi, hemorrhagic fever (e.g. Ebola) and toga with high selectivity. The new compounds are optimized regarding their metabolic stability and with respect to absorption, distribution, metabolism, and excretion properties (ADME) for in vivo testing.

The patented technology is offered for license agreements or transfer of rights, in case an industrial partner intends further in-house development of the technology and its commercialization.

The university involved is also open to discuss a research cooperation with industrial partners in order to further develop the technology together and reach a higher TRL. Agreements on research cooperation would usually include an option for the industrial partner to purchase the patent or obtain a license at later stage.

Advantages & innovations

Cooperation plus value: 
The new DHODH inhibitors offer the following advantages: - high inhibitory effect - antiviral effect - broad spectrum antiviral activity against several RNA viruses - low cytotoxicity - broad therapeutic window - high barrier to resistance of host cell - antiviral therapy of virus infections without addressing viral targets - optimized pharmacokinetics - improved metabolic stability

Stage of development

Cooperation stage dev stage: 
Under development/lab tested

Partner sought

Cooperation area: 
Sought are industrial partners of any size, both SMEs or MNEs, which are focused on the development of chemotherapeutics, virostatics, or antitumoral drugs for treatment of viral infections, autoimmune-diseases or cancer, for licensing, transfer of rights of a pending patent, knowledge transfer, or R&D collaborations. The role of the industrial partner for any type of cooperation would be the commercialisation of the technology. The patented technology is offered for license agreements or transfer of rights, in case an industrial partner intends further in-house development of the technology and its commercialization. The university involved is also open to discuss a research cooperation and knowledge-transfer with industrial partners in order to further develop the technology together and reach a higher TRL. The goal of a possible collaboration could be to test specific DHODH inhibitor candidates in preclinical or clinical trials. Agreements on a research cooperation would usually include an option for the industrial partner to purchase the patent or obtain a license at later stage.

Type and size

Cooperation task: 
SME 11-50,SME <10,>500 MNE,251-500,SME 51-250,>500

fig1.png

Figure 1: General structure of the novel DHODH inhibiting compounds