Identification of Mubritinib (TAK 165) as an inhibitor of KSHV driven primary effusion lymphoma via disruption of mitochondrial OXPHOS metabolism

Calderon, Abram; Soldan, Samantha S.; Leo, Alessandra De; Deng, Zhong; Frase, Drew; Anderson, Emma; Zhang, Yue; Vladimirova, Olga; Lü, Fang; Leung, Jessica C.; Murphy, Maureen E.; Lieberman, Paul M.

doi:10.18632/oncotarget.27815

Cited by 14 publications

(13 citation statements)

References 67 publications

(77 reference statements)

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“…The structure of the LANA DBD alone and in complex with the viral latent replication origin has been solved [76,78], allowing Kirsch and colleagues to discover and optimize new small compounds able to inhibit the binding of LANA to viral DNA in the low micromolar range [79][80][81]. In addition, Mubritinib (TAK165) was identified as a potent inhibitor of LANA-DNA binding and strongly reduced living KSHV PEL cells in vitro and in vivo [82].…”

Section: Antivirals Targeting Other Steps In the Viral Life Cyclementioning

confidence: 99%

Recent Advances in Developing Treatments of Kaposi’s Sarcoma Herpesvirus-Related Diseases

Naimo

Zischke

Schulz

2021

Viruses

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Kaposi-sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8) is the causative agent of several malignancies, including Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). Active KSHV replication has also been associated with a pathological condition called KSHV inflammatory cytokine syndrome (KICS), and KSHV may play a role in rare cases of post-transplant polyclonal lymphoproliferative disorders. Several commonly used herpesviral DNA polymerase inhibitors are active against KSHV in tissue culture. Unfortunately, they are not always efficacious against KSHV-induced diseases. To improve the outcome for the patients, new therapeutics need to be developed, including treatment strategies that target either viral proteins or cellular pathways involved in tumor growth and/or supporting the viral life cycle. In this review, we summarize the most commonly established treatments against KSHV-related diseases and review recent developments and promising new compounds that are currently under investigation or on the way to clinical use.

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Section: Antivirals Targeting Other Steps In the Viral Life Cyclementioning

confidence: 99%

Recent Advances in Developing Treatments of Kaposi’s Sarcoma Herpesvirus-Related Diseases

Naimo

Zischke

Schulz

2021

Viruses

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“…Two studies have shown that in an experimental setting, CRISPR-Cas9 could be used to damage the LANA gene and thus reduce latent virus carriage [ 5 , 6 ]. Other groups have sought to identify small molecules that interfere with LANA-DNA interactions [ 7 , 8 ]. However, these approaches are still at an early experimental stage, and no in vivo studies have been performed.…”

Section: How Does Kshv Infection Lead To Tumorigenesis?mentioning

confidence: 99%

Kaposi's sarcoma-associated herpesvirus at 27

Gaglia

2021

Tumour Virus Research

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Kaposi's sarcoma-associated herpesvirus (KSHV) was discovered 27 years ago and its link to several pathologies – Kaposi's sarcoma, primary effusion lymphoma, and the B cell variant of Multicentric Castleman disease – is now well established. However, many questions remain about how KSHV causes tumors. Here, I will review studies from the last few years (primarily 2019–2021) that report new information about KSHV biology and tumorigenesis, including new results about KSHV proteins implicated in tumorigenesis, genetic and environmental variability in KSHV-related tumor development, and potential vulnerabilities of KSHV-caused tumors that could be novel therapeutic targets.

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“…It is able to activate these drugs during KSHV productive phase by phosphorylation nucleoside analogs. Pyrimidine nucleosides, such as brivudine and azidothymidine (zidovudine, the anti-HIV nucleoside reverse transcriptase inhibitor), are efficiently phosphorylated by KSHV TK [ 66 ].…”

Section: Therapeutics Treatments In Ebv- and -Kshv-infected Malignanciesmentioning

confidence: 99%

“…Kirsch and colleagues demonstrated that some new small molecules inhibited LANA binding to viral genome. One of these therapeutics, mubritinib (TAK165), was used as a LANA-DNA inhibitor in PEL cell treatments in vivo and in vitro [ 66 , 67 ]. The viral FLICE inhibitory protein (vFLIP) binds the IKK/NEMO complex, regulating, in turn, cell cycle progression and apoptosis.…”

Section: Therapeutics Treatments In Ebv- and -Kshv-infected Malignanciesmentioning

confidence: 99%

“…In many studies, an increase of apoptosis in cells treated by Bay 11-7082 was observed—this synthetic drug blockades the vFLIP activation in PEL cells in vitro. In many attempts, RNA interference was used to downregulate the biochemical synthesis of this viral protein to shut down the constitutive expression of the cellular proteins involved in the mitosis and proliferative pathways [ 66 , 67 ]. It is known that the vFLIP complex, with NEMO/IKK and heat shock protein 90 (HSP90), regulate mitogen activated protein kinase (MAPK) phosphorylations.…”

Section: Therapeutics Treatments In Ebv- and -Kshv-infected Malignanciesmentioning

confidence: 99%

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Nanotechnology Frontiers in γ-Herpesviruses Treatments

Granato

2021

IJMS

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Epstein–Barr Virus (EBV) and Kaposi’s sarcoma associated-herpesvirus (KSHV) are γ-herpesviruses that belong to the Herpesviridae family. EBV infections are linked to the onset and progression of several diseases, such as Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC), and lymphoproliferative malignancies arising in post-transplanted patients (PTDLs). KSHV, an etiologic agent of Kaposi’s sarcoma (KS), displays primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). Many therapeutics, such as bortezomib, CHOP cocktail medications, and natural compounds (e.g., quercetin or curcumin), are administrated to patients affected by γ-herpesvirus infections. These drugs induce apoptosis and autophagy, inhibiting the proliferative and cell cycle progression in these malignancies. In the last decade, many studies conducted by scientists and clinicians have indicated that nanotechnology and nanomedicine could improve the outcome of several treatments in γ-herpesvirus-associated diseases. Some drugs are entrapped in nanoparticles (NPs) expressed on the surface area of polyethylene glycol (PEG). These NPs move to specific tissues and exert their properties, releasing therapeutics in the cell target. To treat EBV- and KSHV-associated diseases, many studies have been performed in vivo and in vitro using virus-like particles (VPLs) engineered to maximize antigen and epitope presentations during immune response. NPs are designed to improve therapeutic delivery, avoiding dissolving the drugs in toxic solvents. They reduce the dose-limiting toxicity and reach specific tissue areas. Several attempts are ongoing to synthesize and produce EBV vaccines using nanosystems.

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Identification of Mubritinib (TAK 165) as an inhibitor of KSHV driven primary effusion lymphoma via disruption of mitochondrial OXPHOS metabolism

Cited by 14 publications

References 67 publications

Recent Advances in Developing Treatments of Kaposi’s Sarcoma Herpesvirus-Related Diseases

Recent Advances in Developing Treatments of Kaposi’s Sarcoma Herpesvirus-Related Diseases

Kaposi's sarcoma-associated herpesvirus at 27

Nanotechnology Frontiers in γ-Herpesviruses Treatments

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