ArticleLeukemia2013
Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs.
Article in Leukemia, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
32 citing papers in PubMed, 59 citations in OpenAlex.
- Trial
- SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis.Molecular cell · 2025Article
- Novel Small Molecule Inhibitors of Cyclin-dependent Kinases as Anticancer Agents.Current medicinal chemistry · 2025Review
- Strategy for drug repurposing in fibroadipogenic replacement during muscle wasting: application to duchenne muscular dystrophy.Frontiers in cell and developmental biology · 2025Article
- Centrosomes and associated proteins in pathogenesis and treatment of breast cancer.Frontiers in oncology · 2024Review
- The prognostic role of p53 and its correlation with CDK9 in urothelial carcinoma.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2023Article
- Preclinical assessment of synergistic efficacy of MELK and CDK inhibitors in adrenocortical cancer.Journal of experimental & clinical cancer research : CR · 2022Article
- CDK9 inhibitors in cancer research.RSC medicinal chemistry · 2022Review
- Combination therapy targeting Erk1/2 and CDK4/6i in relapsed refractory multiple myeloma.Leukemia · 2022Article
- Novel CDK9 inhibitor oroxylin A promotes wild-type P53 stability and prevents hepatocellular carcinoma progression by disrupting both MDM2 and SIRT1 signaling.Acta pharmacologica Sinica · 2022Article
- CDK9 inhibitors in multiple myeloma: a review of progress and perspectives.Medical oncology (Northwood, London, England) · 2022Review
- Small molecule inhibitors of cyclin-dependent kinase 9 for cancer therapy.Journal of enzyme inhibition and medicinal chemistry · 2021Review
- Review
- CDK inhibitors in cancer therapy, an overview of recent development.American journal of cancer research · 2021Review
- Review
- Clinical utility of recently identified diagnostic, prognostic, and predictive molecular biomarkers in mature B-cell neoplasms.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2017Review
- Article
- Phytochemical-induced nucleolar stress results in the inhibition of breast cancer cell proliferation.Redox biology · 2017Article
- Cell cycle proteins as promising targets in cancer therapy.Nature reviews. Cancer · 2017Review
- Review
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
Small-molecule multi-targeted cyclin-dependent kinase (CDK) inhibitors (CDKIs) are of particular interest due to their potent antitumor activity independent of p53 gene alterations. P53 deletion is associated with a very poor prognosis in multiple myeloma (MM). In this regard, we tested the anti-MM activity of RGB-286638, an indenopyrazole-derived CDKI with Ki-nanomolar activity against transcriptional CDKs. We examined RGB-286638's mode-of-action in MM cell lines with wild-type (wt)-p53 and those expressing mutant p53. RGB-286638 treatment resulted in MM cytotoxicity in vitro associated with inhibition of MM tumor growth and prolonged survival in vivo. RGB-286638 displayed caspase-dependent apoptosis in both wt-p53 and mutant-p53 cells that was closely associated with the downregulation of RNA polymerase II phosphorylation and inhibition of transcription. RGB-286638 triggered p53 accumulation via nucleolar stress and loss of Mdm2, accompanied by induction of p53 DNA-binding activity. In addition, RGB-286638 mediated p53-independent activity, which was confirmed by cytotoxicity in p53-knockdown and p53-mutant cells. We also demonstrated downregulation of oncogenic miR-19, miR-92a-1 and miR-21. Our data provide the rationale for the development of transcriptional CDKIs as therapeutic agents, which activate p53 in competent cells, while circumventing p53 deficiency through alternative p53-independent cell death mechanisms in p53-mutant/deleted cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.