A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity

Yusenko, Maria V.; Jakobs, Anke; Klempnauer, Karl‐Heinz

doi:10.1038/s41598-018-31620-1

Cited by 24 publications

(26 citation statements)

References 60 publications

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“…This concept was validated by studies of a mouse model of AML and by initial work on small-molecule compounds targeting MYB. These studies confirmed that MYB-inhibitory compounds can significantly prolong leukemia latency in mouse models of AML [ 10 , 12 – 19 ].…”

Section: Discussionsupporting

confidence: 56%

“…This has further stimulated interest in MYB as a target for drug development as such a drug would allow the elimination of the leukemia cells while sparing normal hematopoiesis [ 2 , 11 ]. Initial approaches based on small-molecule inhibitors of MYB have already yielded promising results, confirming that leukemia cells are more sensitive to targeting MYB than normal HPCs [ 12 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

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C/EBPβ is a MYB- and p300-cooperating pro-leukemogenic factor and promising drug target in acute myeloid leukemia

et al. 2021

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Transcription factor MYB has recently emerged as a promising drug target for the treatment of acute myeloid leukemia (AML). Here, we have characterized a group of natural sesquiterpene lactones (STLs), previously shown to suppress MYB activity, for their potential to decrease AML cell proliferation. Unlike what was initially thought, these compounds inhibit MYB indirectly via its cooperation partner C/EBPβ. C/EBPβ-inhibitory STLs affect the expression of a large number of MYB-regulated genes, suggesting that the cooperation of MYB and C/EBPβ broadly shapes the transcriptional program of AML cells. We show that expression of GFI1, a direct MYB target gene, is controlled cooperatively by MYB, C/EBPβ, and co-activator p300, and is down-regulated by C/EBPβ-inhibitory STLs, exemplifying that they target the activity of composite MYB-C/EBPβ-p300 transcriptional modules. Ectopic expression of GFI1, a zinc-finger protein that is required for the maintenance of hematopoietic stem and progenitor cells, partially abrogated STL-induced myelomonocytic differentiation, implicating GFI1 as a relevant target of C/EBPβ-inhibitory STLs. Overall, our data identify C/EBPβ as a pro-leukemogenic factor in AML and suggest that targeting of C/EBPβ may have therapeutic potential against AML.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

C/EBPβ is a MYB- and p300-cooperating pro-leukemogenic factor and promising drug target in acute myeloid leukemia

et al. 2021

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“…All cell lines were originally obtained from ATCC and are free of mycoplasma contamination. HL60 cells expressing a C-terminally truncated MYB (MYB-CT3) and control HL60 cells were generated by lentiviral infection as described previously [ 43 , 45 ]. AML cells were grown in RPMI1640 medium supplemented with 10% FCS.…”

Section: Methodsmentioning

confidence: 99%

“…We have screened chemical compound libraries for low molecular weight MYB inhibitors, using a previously established MYB reporter cell line [ 42 , 43 , 44 ]. Here, we present the initial characterization of 2-amino-4-(3,4,5-trimethoxyphenyl)-4 H -naphtho[1,2- b ]pyran-3-carbonitrile (Bcr-TMP), a novel and highly active MYB-inhibitory compound.…”

Section: Introductionmentioning

confidence: 99%

Bcr-TMP, a Novel Nanomolar-Active Compound That Exhibits Both MYB- and Microtubule-Inhibitory Activity

Yusenko

Biyanee

Frank

et al. 2021

Cancers

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Studies of the role of MYB in human malignancies have highlighted MYB as a potential drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Here, we present the initial characterization of 2-amino-4-(3,4,5-trimethoxyphenyl)-4H-naphtho[1,2-b]pyran-3-carbonitrile (Bcr-TMP), a nanomolar-active MYB-inhibitory compound identified in a screen for novel MYB inhibitors. Bcr-TMP affects MYB function in a dual manner by inducing its degradation and suppressing its transactivation potential by disrupting its cooperation with co-activator p300. Bcr-TMP also interferes with the p300-dependent stimulation of C/EBPβ, a transcription factor co-operating with MYB in myeloid cells, indicating that Bcr-TMP is a p300-inhibitor. Bcr-TMP reduces the viability of AML cell lines at nanomolar concentrations and induces cell-death and expression of myeloid differentiation markers. It also down-regulates the expression of MYB target genes and exerts stronger anti-proliferative effects on MYB-addicted primary murine AML cells and patient-derived ACC cells than on their non-oncogenic counterparts. Surprisingly, we observed that Bcr-TMP also has microtubule-disrupting activity, pointing to a possible link between MYB-activity and microtubule stability. Overall, Bcr-TMP is a highly potent multifunctional MYB-inhibitory agent that warrants further investigation of its therapeutic potential and mechanism(s) of action.

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“…Podophyllotoxin derivatives showed promising cytotoxicities against a set of human cancer cell lines HL-60 [267]. Teniposide and etoposide have been reported as inhibitors of MYB transcription factor [268]. GMZ-1 suppresses growth and induces apoptosis in adriamycinresistant K562/A02 cells through modulation of MDR1 expression [269].…”

Section: Podophyllotoxinsmentioning

confidence: 99%

Complementary and Alternative Treatments for Cancer Prevention and Cure [Part 1]

Mohiuddin¹

2019

JCRCT

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Many lay people along with some so called “key opinion leaders” have a common slogan “There's no answer for cancer”. Again, mistake delays proper treatment and make situation worse, more often. Compliance is crucial to obtain optimal health outcomes, such as cure or improvement in QoL. Patients may delay treatment or fail to seek care because of high out-of- pocket expenditures. Despite phenomenal development, conventional therapy falls short in cancer management. There are two major hurdles in anticancer drug development: dose-limiting toxic side effects that reduce either drug effectiveness or the QoL of patients and complicated drug development processes that are costly and time consuming. Cancer patients are increasingly seeking out alternative medicine and might be reluctant to disclose its use to their oncology treatment physicians. But there is limited available information on patterns of utilization and efficacy of alternative medicine for patients with cancer. As adjuvant therapy, many traditional medicines shown efficacy against brain, head and neck, skin, breast, liver, pancreas, kidney, bladder, prostate, colon and blood cancers. The literature reviews non-pharmacological interventions used against cancer, published trials, systematic reviews and meta-analyses.

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A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity

Cited by 24 publications

References 60 publications

C/EBPβ is a MYB- and p300-cooperating pro-leukemogenic factor and promising drug target in acute myeloid leukemia

C/EBPβ is a MYB- and p300-cooperating pro-leukemogenic factor and promising drug target in acute myeloid leukemia

Bcr-TMP, a Novel Nanomolar-Active Compound That Exhibits Both MYB- and Microtubule-Inhibitory Activity

Complementary and Alternative Treatments for Cancer Prevention and Cure [Part 1]

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