DHODH inhibitors(Dihydroorotate dehydrogenase inhibitors), DHODH modulators(Dihydroorotate dehydrogenase modulators), HOXA9 modulators(homeobox A9 modulators)

Therapeutic Areas

Infectious DiseasesRespiratory Diseases

Active Indication

COVID-19

Inactive Indication

Adult Acute Myeloblastic Leukemia

Originator Organization

Harvard UniversityThe General Hospital Corp.

Shanghai Schering Plough Pharmaceutical Co. Ltd.

Active Organization

University of Sao Paulo

Inactive Organization

Shanghai Schering Plough Pharmaceutical Co. Ltd.The General Hospital Corp.

Harvard University

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with ML390

100 Translational Medicine associated with ML390

100 Patents (Medical) associated with ML390

Literatures (Medical) associated with ML390

12 Mar 2024·ACS Omega

Unveiling the Antiviral Capabilities of Targeting Human Dihydroorotate Dehydrogenase against SARS-CoV-2

Article

Author: Leite, Juliana Almeida ; Souza, Thiago M L ; Silvac, Meryck F B ; Salazar Alvarez, Luis Carlos ; Nonato, M Cristina ; Cruz, Luiza V ; Sacramento, Carolina Q ; Fintelman-Rodrigues, Natalia ; Andrade, Carolina Horta ; Temerozo, Jairo R ; Freitas, Murillo V ; de Freitas, Caroline Souza ; Lopez, Renata F V ; Costa, Fabio T M ; Vaidergorn, Miguel Menezes ; Silva-Mendonça, Sabrina ; Purificação, Aline D ; da Silva Emery, Flavio ; Martin, Bianca A ; Godoi, Bruna Fleck ; Neves, Bruno J

The urgent need for effective treatments against emerging viral diseases, driven by drug-resistant strains and new viral variants, remains critical. We focus on inhibiting the human dihydroorotate dehydrogenase (HsDHODH), one of the main enzymes responsible for pyrimidine nucleotide synthesis. This strategy could impede viral replication without provoking resistance. We evaluated naphthoquinone fragments, discovering potent HsDHODH inhibition with IC₅₀ ranging from 48 to 684 nM, and promising in vitro anti-SARS-CoV-2 activity with EC₅₀ ranging from 1.2 to 2.3 μM. These compounds exhibited low toxicity, indicating potential for further development. Additionally, we employed computational tools such as molecular docking and quantitative structure-activity relationship (QSAR) models to analyze protein-ligand interactions, revealing that these naphthoquinones exhibit a protein binding pattern similar to brequinar, a potent HsDHODH inhibitor. These findings represent a significant step forward in the search for effective antiviral treatments and have great potential to impact the development of new broad-spectrum antiviral drugs.

01 Jan 2023·Antiviral Research

ML390 inhibits enterovirus 71 replication by targeting de novo pyrimidine biosynthesis pathway

Article

Author: Yang, Qingyu ; Huang, Rui ; Zhang, Dingyu ; Zhu, Guangyan ; Lin, Binbin ; Peng, Ke ; Wang, Qiongya ; Huang, Chaolin ; Wu, Chengyuan ; Ren, Fuli ; Hu, Xujuan ; Wu, Ying ; Zhao, Dingran

Enterovirus 71 (EV71), a small, single-stranded, positive-sense RNA virus belonging to the enterovirus genus in the family Picornaviridae, causes hand, foot, and mouth disease. Although EV71 seriously threatens to public health, no effective antiviral drugs are available for treating this disease. In this study, we found that ML390, a dihydroorotate dehydrogenase inhibitor, has potential anti-EV71 activity. ML390 dose-dependently inhibited EV71 replication with IC₅₀ and selectivity index values of 0.06601 μM and 156.5, respectively. Supplementation with the downstream product orotate significantly suppressed the ability of ML390 to inhibit EV71 replication. Moreover, an adequate supply of exogenous uridine and cytosine suppressed the anti-EV71 activity of ML390. Thus, the antiviral activity of ML390 is mediated by the inhibition of the pyrimidine synthesis pathway. In an EV71-infected mouse model, ML390 reduced the load of EV71 in the brain, liver, heart, spleen, front legs, and hind legs, and significantly increased the survival rate of the mice infected by EV71. ML390 shows potential for the treatment of hand, foot, and mouth disease caused by EV71 infection.

01 Oct 2022·Journal of Medical Virology

Identification of clinical candidates against West Nile virus by activity screening in vitro and effect evaluation in vivo

Article

Author: Tang, Hailin ; Ren, Ruiwen ; Liu, Yan ; Qi, Zhongtian ; He, Yanhua ; Zhao, Ping ; Liu, Yang ; Peng, Haoran

AbstractThe West Nile virus (WNV) is a member of the flavivirus and is known to cause encephalitis. There is currently no specific treatment for WNV infection. Repurposing of clinically approved drugs appeared promising for rapidly identifying effective, safe, and readily available candidates for antiviral drugs. Here, we screened the small‐molecule compounds with anti‐WNV activity from 978 Food Drug Administration‐approved drugs. Four compounds, including cilnidipine, mycophenolate mofetil, nitazoxanide, and teriflunomide, were found to efficiently abrogate WNV infection in Vero cells and human neuroblastoma SH‐SY5Y cells. The four compounds also exert broad‐spectrum antiviral activity against the Zika virus, Japanese encephalitis virus, yellow fever virus, tick‐borne encephalitis virus, and chikungunya virus. Furthermore, nitazoxanide (a synthetic benzamide) and teriflunomide (an inhibitor of dihydroorotate dehydrogenase, DHODH) protected 20% and 40% of mice from lethal WNV challenge, respectively. Both drugs, which are orally bioavailable and have been approved clinically for many years, may be promising therapeutics for WNV infection. Moreover, the other two DHODH inhibitors, ML390 and vidofludimus, also displayed potent activity against WNV infection in vitro and in vivo.

100 Deals associated with ML390

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
COVID-19	Preclinical	Brazil	University of Sao Paulo	28 Feb 2024
Adult Acute Myeloblastic Leukemia	Discovery	United States	The General Hospital Corp.	22 Sep 2016
Adult Acute Myeloblastic Leukemia	Discovery	United States	Harvard University	22 Sep 2016
Adult Acute Myeloblastic Leukemia	Discovery	China	Shanghai Schering Plough Pharmaceutical Co. Ltd.	22 Sep 2016

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