US-12616671-B2 - Use of rigosertib to treat RNA virus infections

Abstract

Provided herein are methods for treating a virus (e.g,. an RNA virus, such as a SARS-CoV-2) infection or a disease associated therewith (e.g., COVID-19) comprising administering Rigosertib or a composition thereof to a subject (e.g., a human subject).

Inventors

• Premkumar Reddy
• Kris White
• M.V. Ramana Reddy
• Adolfo Garcia-Sastre

Assignees

• ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI

Dates

Publication Date

20260505

Application Date

20210528

Claims (4)

1. 1 . A method for treating a SARS-COV-2 infection or COVID-19, comprising administering to the subject an effective amount of Rigosertib to a human subject in need thereof.
2. 2 . The method according to claim 1 , wherein the rigosertib is administered at a dosage of 280 mg, 560 mg, 840 mg or 1120 mg.
3. 3 . The method according to claim 2 , wherein the rigosertib dosage is administered once or twice per day.
4. 4 . The method according to claim 3 , wherein the rigosertib dosage is administered once per day.

Description

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under HHSN272201400008C and U19AI135972 awarded by the NIAID and NIH. The government has certain rights in the invention. FIELD OF THE INVENTION The present invention relates to compositions and methods for treating RNA virus infections or diseases associated therewith. More particularly, the present invention is directed to the treatment of SARS-CoV-2 and other viral infections by administration of rigosertib. 1. BACKGROUND There is an urgent need to develop therapeutics to treat COVID-19 and diagnostics to detect severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As of May 26 2020, more than 5,550,399 people globally have tested positive for SARS-CoV-2. In addition, as of May 26, 2020, globally more than 348,302 people have died from COVID-19. Currently, there is no approved vaccine or therapeutic to prevent or treat COVID-19. Rigosertib (otherwise known as ON01910. Na) is a synthetic benzyl styryl sulfone substance, previously developed as an anticancer agent, and has recently completed Phase III clinical trials for the treatment of Myelodysplastic Syndrome (MDS). (See U.S. Pat. No. 7,598,232), myelodysplastic syndrome and acute myeloid leukemia (U.S. Pat. No. 8,664,272). Rigosertib is a small molecule RAS-mimetic that suppresses RAS-mediated signaling pathways (Athuluri-Divakar et al., A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell. 2016; 165(3):643-655. doi:10.1016/j.cell.2016.03.045) and thus acts as a suppressor of multiple cellular signaling pathways. Rigosertib is a water-soluble compound that is orally bio-available with little or no toxic side effects and has been used to treat over 1000 patients in clinical trials. Thus, its Absorption, Distribution, Metabolism, Excretion and Toxicity profiles in human subjects is well established. Drug repurposing is aimed at developing new indications for drugs currently in use and is recognized as an important approach to rapidly develop new treatments for unrelated diseases. This approach of drug repurposing reduces the cost and duration of new drug development since the safety profile of the compound is well established from earlier clinical trials. Drug repurposing has the following advantages: (1) the use, preparation and stability of the drug candidate established; (2) Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET), are established; (3) the probability of failure due to safety issues is significantly lower because of the available clinical trial data; (4) Time required for Post-marketing Surveillance (PMS) is greatly diminished. 2. SUMMARY In one aspect, provided herein is the use of Rigosertib as an antiviral (e.g., an antiviral for RNA virus infections). The use of Rigosertib as an antiviral is based, in part, on the discovery that it inhibits the replication of SARS-CoV-2, a positive-sense single-stranded RNA virus. See Section 5, infra. RNA viruses utilize cellular signaling machinery for their replication and virus assembly, suggesting that inhibition of one or more of these signaling pathways could result in the inhibition of viral replication. For example, SARS-CoV-2 infection is initiated by the interaction of viral spike protein with host cell surface receptors such as Angiotensin-converting enzyme 2 (ACE2) or CD147. This event results in the fusion of cellular and viral membranes leading to the release of viral genome into the cellular cytoplasm. Infection of lung epithelial cells with SARS-CoV-2 induces the activation of multiple signaling pathways leading to enhanced replication of the virus as well as several pathogenic events associated with coronavirus infection (Gordon et al., 2020, A SARS-CoV-2 protein interaction map reveals targets for drug repurposing [published online ahead of print, 2020 Apr. 30]. Nature. 2020; 10.1038/s41586-020-2286-9. doi:10.1038/s41586-020-2286-9). Rigosertib is a small molecule RAS-mimetic that suppresses RAS-mediated signaling pathways (Athuluri-Divakar et al., A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell. 2016; 165(3):643-655. doi:10.1016/j.cell.2016.03.045) and thus acts as a suppressor of multiple cellular signaling pathways. Since mutations in the viral genome do not have an effect on cellular signaling machinery, the use of Rigosertib as an antiviral avoids development of resistance to the drug as a result of mutations in the virus. In another aspect, provided herein are methods for treating a virus infection or a disease associated therewith, comprising administering Rigosertib to a subject in need thereof. In one embodiment, provided herein is a method for treating an RNA virus infection or a disease associated therewith comprising administering Rigosertib to a subject in need thereof. The RNA virus may be single stranded or double-stranded, positive or negative sense, a