Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors

Liu, Shuai; Yosief, Hailemichael O.; Dai, Lingling; Huang, He; Dhawan, Gagan; Zhang, Xiaofeng; Muthengi, Alex; Roberts, Justin M.; Buckley, Dennis L.; Perry, Jennifer A.; Wu, Lang; Bradner, James E.; Qi, Jun; Zhang, Wei

doi:10.1021/acs.jmedchem.8b00765

Cited by 51 publications

(50 citation statements)

References 43 publications

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“…Considering the relevance of BRD4 inhibition for shock as well as PLK1 inhibition for kill, we expect that such PLK1-BET dual inhibitors would be useful for the shock-and-kill HIV-1 cure approach. Initially, we screened 24 PLK1-BET dual inhibitors with novel scaffolds (UMB series) ( 42 ) to identify candidates with potent capability to reactivate latent HIV-1 in J-Lat A2 cells. We identified three candidates, UMB-151, UMB-156, and UMB-158, which have strong latency-reversing potency but weak cytotoxicity ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of Polo-like kinase 1 (PLK1) facilitates the elimination of HIV-1 viral reservoirs in CD4 ⁺ T cells ex vivo

et al. 2020

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Although combination antiretroviral therapy is effective in controlling HIV-1 infection, latent HIV-1 proviruses cannot be eliminated. HIV-1 reactivation induced by the mere use of latency-reversing agents is insufficient to render death of reservoir cells, indicating that certain intrinsic survival mechanisms exist. We report that Polo-like kinase 1 (PLK1) plays a critical role in survival of CD4+ T cells that undergo HIV-1 reactivation from latency or de novo infection. PLK1 is elevated in both scenarios, which requires HIV-1 Nef. HIV-1 enhances PLK1 SUMOylation, causing its nuclear translocation and protein stabilization. Inhibition or knockdown of PLK1 markedly facilitates death of HIV-1-infected CD4+ T cells. Furthermore, PLK1 inhibitors strikingly reduce the size of HIV-1 latent reservoirs in primary CD4+ T cells. Our findings demonstrate that HIV-1 infection hijacks PLK1 to prevent cell death induced by viral cytopathic effects, and that PLK1 is a promising target for chemical “killing” of HIV-1 reservoir cells.

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Section: Resultsmentioning

confidence: 99%

“…Recombinant HIV-1 Nef protein (rNef) and cART compounds (nevirapine, raltegravir, zidovudine, and efavirenz) were provided by NIH AIDS reagent program. The UMB series of PLK1-BET dual inhibitors were synthesized according to an earlier publication (42). The following antibodies were used in this study.…”

Section: Compounds and Antibodiesmentioning

confidence: 99%

Inhibition of Polo-like kinase 1 (PLK1) facilitates the elimination of HIV-1 viral reservoirs in CD4 ⁺ T cells ex vivo

et al. 2020

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“…Recently, PLK1-BET dual inhibitors have been developed to target both PLK1 and BRD4, two major protein targets in anticancer therapies 394041 . We tested one of such PLK1-BET dual inhibitors, UMB158, which possesses the novel scaffold (UMB series) 28 , previously studied by our group. Indeed, UMB158 treatment also promotes the Dox-induced KSHV reactivation in iSLK.r219 cells at the lower dose compared to SBE ( Fig 3F ).…”

Section: Resultsmentioning

confidence: 99%

“…Recombinant HIV-1 Nef protein (rNEF) were provided by NIH AIDS reagent program. The UMB-158 PLK1-BET dual inhibitor was synthesized according to an earlier publication 28 . The STAT3 inhibitor, Cryptotansinone and Stattic, were purchased from Sigma-Aldrich.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of polo-like kinase 1 (PLK1) facilitates reactivation of gamma-herpesviruses in B-cell lymphomas and their elimination

Biswas

Fiches

Zhou

et al. 2020

Preprint

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Both Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) can establish the persistent, life-long infection primarily at the latent status, and contribute to certain types of tumors, including B cell lymphomas, especially in immuno-compromised individuals, such as people living with HIV (PLWH). Lytic reactivation of these viruses can be employed to kill tumor cells harboring latently infected viral episomes, through the viral cytopathic effects and the subsequent antiviral immune responses. In this study, we identified that expression of Polo-like kinase 1 (PLK1) in B cells is elevated in the context of HIV infection and by HIV Nef protein. We further demonstrated that PLK1 depletion or inhibition can promote KSHV reactivation and cell death of KSHV-reactivated tumor cells. Mechanistically, PLK1 regulates Myc protein that is critical for both maintenance of KSHV latency and support of cell survival, and affects the level of H3K27me3 suppressive mark both globally and at certain loci of KSHV viral episomes. Lastly, we recognized that PLK1 inhibition can synergize with STAT3 inhibition to induce efficient KSHV reactivation. PLK1 depletion or inhibition yielded the similar effect on promoting EBV reactivation and cell death of EBV-reactivated tumor cells. Our findings illustrated that PLK1 is a novel host target that can be inhibited to benefit the viral oncolysis to eliminate KSHV/EBV-infected tumor cells.

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“…In recent years, small molecule inhibitors with dual-targeting activity have been described [[26], [27], [28]]. Intriguingly, some PLK1 kinase inhibitors can simultaneously inhibit BET protein bromodomains [[29], [30], [31], [32], [33], [34]]. Here, we extend previous evidence that combination of BRD4 and PLK1 inhibitors has synergistic antitumor effects in pediatric tumor models and provide evidence for the therapeutic activity of recently developed dual-targeting BRD4 and PLK1 inhibitors in preclinical models of pediatric tumors.…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors

Timme

Han

Liu

et al. 2020

Translational Oncology

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Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models.

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Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors

Cited by 51 publications

References 43 publications

Inhibition of Polo-like kinase 1 (PLK1) facilitates the elimination of HIV-1 viral reservoirs in CD4 ⁺ T cells ex vivo

Inhibition of Polo-like kinase 1 (PLK1) facilitates the elimination of HIV-1 viral reservoirs in CD4 ⁺ T cells ex vivo

Inhibition of polo-like kinase 1 (PLK1) facilitates reactivation of gamma-herpesviruses in B-cell lymphomas and their elimination

Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors

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Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors

Cited by 51 publications

References 43 publications

Inhibition of Polo-like kinase 1 (PLK1) facilitates the elimination of HIV-1 viral reservoirs in CD4 + T cells ex vivo

Inhibition of Polo-like kinase 1 (PLK1) facilitates the elimination of HIV-1 viral reservoirs in CD4 + T cells ex vivo

Inhibition of polo-like kinase 1 (PLK1) facilitates reactivation of gamma-herpesviruses in B-cell lymphomas and their elimination

Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors

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Inhibition of Polo-like kinase 1 (PLK1) facilitates the elimination of HIV-1 viral reservoirs in CD4 ⁺ T cells ex vivo

Inhibition of Polo-like kinase 1 (PLK1) facilitates the elimination of HIV-1 viral reservoirs in CD4 ⁺ T cells ex vivo