Novel dual-targeting c-Myc inhibitor D347-2761 represses myeloma growth via blocking c-Myc/Max heterodimerization and disturbing its stability
Open accessAbstract
Background: Transcription factor c-Myc plays a critical role in various physiological and pathological events. c-Myc gene rearrangement is closely associated with multiple myeloma (MM) progression and drug resistance. Thereby, targeting c-Myc is expected to be a useful therapeutic strategy for hematological disease, especially in MM. Methods: Molecular docking-based virtual screening and dual-luciferase reporter gene assay were used to identify novel c-Myc inhibitors. Cell viability and flow cytometry were performed for evaluating myeloma cytotoxicity. Western blot, immunofluorescence, immunoprecipitation, GST pull down and Electrophoretic Mobility Shift Assay were performed for protein expression and interaction between c-Myc and Max. c-Myc downstream targets were measured by Q-PCR and Chromatin immunoprecipitation methods. Animal experiments were used to detect myeloma xenograft and infiltration in vivo. Results: We successfully identified a novel c-Myc inhibitor D347-2761, which hindered the formation of c-Myc/Max heterodimer and disturbed c-Myc protein stability simultaneously. Compound D347-2761 dose-and time-dependently inhibited myeloma cell proliferation and induced apoptosis. Dual knockout Bak/Bax partially restored D347-2761-mediated cell death. Additionally, compound D347-2761 could, in combination with bortezomib (BTZ), enhance MM cell DNA damage and overcome BTZ drug resistance. Our in vivo studies also showed that compound D347-2761 repressed myeloma growth and distal infiltration by downregulating c-Myc expression. Mechanistically, novel dual-targeting c-Myc inhibitor D347-2761 promoted c-Myc protein degradation via stimulating c-Myc Thr58 phosphorylation levels, which ultimately led to transcriptional repression of CDK4 promoter activity. Conclusions: We identified a novel dual-targeting c-Myc small molecular inhibitor D347-2761. And this study may provide a solid foundation for developing a novel therapeutic agent targeting c-Myc.
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D347-2761 influences the heterodimerization of c-Myc and Max, thereby affecting the stability of c-Myc and regulating downstream targeted genes.
“It also influences the heterodimerization of c-Myc and Max, thereby affecting the stability of c-Myc and regulating downstream targeted genes.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [474]
In a mouse model of osteosarcoma, D347-2761 inhibited tumor growth and reduced the expression level of Myc.
“In a mouse model of osteosarcoma, D347-2761 inhibited tumor growth and reduced the expression level of Myc.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [474]
In activity characterization experiment, D347-2761 bound to the DNA-binding region of Myc protein and demonstrated proliferation inhibitory activity on myeloma cells at 5-10 μM, with no inhibitory effect on normal cells.
“In activity characterization experiment, D347-2761 bound to the DNA-binding region of Myc protein and demonstrated proliferation inhibitory activity on myeloma cells at 5–10 μM, with no inhibitory effect on normal cells.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [474]
D347-2761 induced cell death by promoting apoptosis.
“The compound induced cell death by promoting apoptosis.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [474]
In 2022, Xu Kelin's research group employed molecular docking and screening in a compound library based on the crystal structure of the c-Myc/Max complex, and conducted experimental screening of the resulting compounds, leading to the identification of the most active compound D347-2761 (best activity at 10 μM).
“In 2022, Xu Kelin’s research group employed molecular docking and screening in a compound library based on the crystal structure of the c-Myc/Max complex, and conducted experimental screening of the resulting compounds, leading to the identification of the most active compound D347-2761 (194) (best activity at 10 μM) (Table 3).474”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [474]
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- Authors
- Yao, R., Zhang, M., Zhou, J., Liu, L., Zhang, Y., Gao, J., & Xu, K.
- Affiliations
- Xuzhou Medical College (CN)
- Corresponding author
- Gao, Jian
- Xu, Kailin
- Venue
- Cell Communication and Signaling
- Published
- 2022-05-26
- Volume
- 20
- Issue
- 1
- Pages
- 73-73
- ISSN
- 1478-811X (ISSN-L)
- PMC
- PMC9137135
- OpenAlex
- W4281572042
- Cited by
- 32
- References
- 41
- Citations by year
- 2026: 10 · 2025: 5 · 2024: 8 · 2023: 9
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Communication and Signaling (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Government of Jiangsu Province (YY-046)
- Natural Science Foundation of Jiangsu Province (BK20201152)
- Six Talent Peaks Project in Jiangsu Province (YY-046)
- Xuzhou Medical University
- Qinglan Project of Jiangsu Province of China
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- c-Myc, multiple myeloma, bortezomib resistance, apoptosis, drug resistance
- MeSH terms
- Bortezomib, Animals, Antineoplastic Agents, Humans, Multiple Myeloma, Proto-Oncogene Proteins c-myc, Cell Line, Tumor, Molecular Docking Simulation
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