CDK9 inhibitor FIT-039 prevents replication of multiple DNA viruses

Yamamoto, Makoto; Onogi, Hiroshi; Kii, Isao; Yoshida, Suguru; Iida, Kei; Sakai, Hiroyuki; Abe, Mitsunari; Tsubota, Toshiaki; Ito, Nobuyasu; Hosoya, Takamitsu; Hagiwara, Masatoshi

doi:10.1172/jci73805

Cited by 68 publications

(80 citation statements)

References 49 publications

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“…Pharmacological CDKis have been shown to inhibit replication of diverse viruses in culture, including herpes viruses and HIV 41–46 , and depletion of CDK9 impairs influenza A viral replication 47 . The possibility of ZIKV inhibition by a CDKi is particularly intriguing, given our recent observation that ZIKV infection and cell cycle regulation are intimately connected 15 .…”

Section: Resultsmentioning

confidence: 99%

Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen

Lee

Wen

et al. 2016

Nat Med

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535

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In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ~6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds, and we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, Emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and 3-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, an FDA approved category B anthelmintic drug, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.

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Section: Resultsmentioning

confidence: 99%

Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen

Lee

Wen

et al. 2016

Nat Med

599

535

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show abstract

“…1) is a novel and small-molecule CDK9 inhibitor recently identified (Yamamoto et al, 2014). It inhibited replication of a broad spectrum of DNA viruses, including herpes simplex virus type 1 (HSV-1), HSV-2, human adenovirus, and human cytomegalovirus, in cell cultures.…”

Section: Short Communication (Revised Manuscript)mentioning

confidence: 99%

Selective inhibition of HIV-1 replication by the CDK9 inhibitor FIT-039

et al. 2015

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“…CDK1, CDK2, CDK7, and CDK9 have been shown to activate and promote replication and transcription in different DNA viruses, including HAdV. An example of an inhibitor that suppress the replication of HAdV is FIT-039 (N-[5-fluoro-2-(1-piperidinyl)phenyl]isonicotinthioamide), obtained from the screening of a synthetic chemical library of small molecules looking for compounds that suppressed the activity of CDK9 [113]. This molecule had an IC50 value of 5.8 MM against the kinase activity of CDK9/cyclin T1 in vitro and also demonstrated potent replication inhibitory activity of a broad spectrum of DNA viruses by the blockage of mRNA transcription [113].…”

Section: Host Targets For Drug Discoverymentioning

confidence: 99%