Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule
1,25-Dihydroxyvitamin D (1,25D) analogs engage the vitamin D receptor (VDR) and can exert anticancer and immunomodulatory effects. Although tumors often resist 1,25D monotherapy, combining VDR agonism with histone deacetylase inhibitors (HDACi) restores anticancer efficacy. Here, we present AC-340,...
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| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , , , |
| منشور في: |
2025
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| الموضوعات: | |
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| _version_ | 1852016463036022784 |
|---|---|
| author | Fatemeh Sarmadi (18865539) |
| author2 | Amelia Caza (22273467) Zhizhong Gao (18865542) Natacha Rochel (225991) James L. Gleason (1853971) John H. White (63329) |
| author2_role | author author author author author |
| author_facet | Fatemeh Sarmadi (18865539) Amelia Caza (22273467) Zhizhong Gao (18865542) Natacha Rochel (225991) James L. Gleason (1853971) John H. White (63329) |
| author_role | author |
| dc.creator.none.fl_str_mv | Fatemeh Sarmadi (18865539) Amelia Caza (22273467) Zhizhong Gao (18865542) Natacha Rochel (225991) James L. Gleason (1853971) John H. White (63329) |
| dc.date.none.fl_str_mv | 2025-09-19T02:55:31Z |
| dc.identifier.none.fl_str_mv | 10.1021/acs.jmedchem.5c01932.s002 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/dataset/Hyperagonism_of_a_Vitamin_D_Receptor_Agonist_Histone_Deacetylase_Inhibitor_Hybrid_Molecule/30162201 |
| dc.rights.none.fl_str_mv | CC BY-NC 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biophysics Biochemistry Medicine Cell Biology Genetics Molecular Biology Pharmacology Developmental Biology Cancer Virology Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified novel bifunctional molecule multiple melanoma models multiple cancer models histone deacetylase inhibitors elevated h3k27 acetylation comparative structural studies restores anticancer efficacy vdr target genes combining vdr agonism vdr agonist backbone 340 hdaci activity exert anticancer vdr hyperagonist robust bifunctionality rnaseq analysis receptor agonist qpcr revealed likely coupled incorporates hdaci immunomodulatory effects combination therapies coactivator cbp broad array analogs engage active transcription 340 superinduces 340 functions 340 forms |
| dc.title.none.fl_str_mv | Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule |
| dc.type.none.fl_str_mv | Dataset info:eu-repo/semantics/publishedVersion dataset |
| description | 1,25-Dihydroxyvitamin D (1,25D) analogs engage the vitamin D receptor (VDR) and can exert anticancer and immunomodulatory effects. Although tumors often resist 1,25D monotherapy, combining VDR agonism with histone deacetylase inhibitors (HDACi) restores anticancer efficacy. Here, we present AC-340, a novel bifunctional molecule that incorporates HDACi into a VDR agonist backbone. Besides its robust bifunctionality in vitro in multiple melanoma models, RNaseq analysis of B16–F10 mouse melanoma cells revealed that AC-340 superinduces the expression of a broad array of VDR target genes. Comparative structural studies and ChIP-qPCR revealed that AC-340 forms more interactions than 1,25D with residues in the VDR coactivator binding domain, leading to more efficacious recruitment of coactivator CBP. This, likely coupled with AC-340 HDACi activity, leads to elevated H3K27 acetylation of VDR target genes, a mark of active transcription. Thus, AC-340 functions as a VDR hyperagonist and should be efficacious in mono- or combination therapies against multiple cancer models. |
| eu_rights_str_mv | openAccess |
| id | Manara_b01bb7d64aab28a5f716ffecd41dc34d |
| identifier_str_mv | 10.1021/acs.jmedchem.5c01932.s002 |
| network_acronym_str | Manara |
| network_name_str | ManaraRepo |
| oai_identifier_str | oai:figshare.com:article/30162201 |
| publishDate | 2025 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY-NC 4.0 |
| spelling | Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid MoleculeFatemeh Sarmadi (18865539)Amelia Caza (22273467)Zhizhong Gao (18865542)Natacha Rochel (225991)James L. Gleason (1853971)John H. White (63329)BiophysicsBiochemistryMedicineCell BiologyGeneticsMolecular BiologyPharmacologyDevelopmental BiologyCancerVirologyBiological Sciences not elsewhere classifiedChemical Sciences not elsewhere classifiednovel bifunctional moleculemultiple melanoma modelsmultiple cancer modelshistone deacetylase inhibitorselevated h3k27 acetylationcomparative structural studiesrestores anticancer efficacyvdr target genescombining vdr agonismvdr agonist backbone340 hdaci activityexert anticancervdr hyperagonistrobust bifunctionalityrnaseq analysisreceptor agonistqpcr revealedlikely coupledincorporates hdaciimmunomodulatory effectscombination therapiescoactivator cbpbroad arrayanalogs engageactive transcription340 superinduces340 functions340 forms1,25-Dihydroxyvitamin D (1,25D) analogs engage the vitamin D receptor (VDR) and can exert anticancer and immunomodulatory effects. Although tumors often resist 1,25D monotherapy, combining VDR agonism with histone deacetylase inhibitors (HDACi) restores anticancer efficacy. Here, we present AC-340, a novel bifunctional molecule that incorporates HDACi into a VDR agonist backbone. Besides its robust bifunctionality in vitro in multiple melanoma models, RNaseq analysis of B16–F10 mouse melanoma cells revealed that AC-340 superinduces the expression of a broad array of VDR target genes. Comparative structural studies and ChIP-qPCR revealed that AC-340 forms more interactions than 1,25D with residues in the VDR coactivator binding domain, leading to more efficacious recruitment of coactivator CBP. This, likely coupled with AC-340 HDACi activity, leads to elevated H3K27 acetylation of VDR target genes, a mark of active transcription. Thus, AC-340 functions as a VDR hyperagonist and should be efficacious in mono- or combination therapies against multiple cancer models.2025-09-19T02:55:31ZDatasetinfo:eu-repo/semantics/publishedVersiondataset10.1021/acs.jmedchem.5c01932.s002https://figshare.com/articles/dataset/Hyperagonism_of_a_Vitamin_D_Receptor_Agonist_Histone_Deacetylase_Inhibitor_Hybrid_Molecule/30162201CC BY-NC 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/301622012025-09-19T02:55:31Z |
| spellingShingle | Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule Fatemeh Sarmadi (18865539) Biophysics Biochemistry Medicine Cell Biology Genetics Molecular Biology Pharmacology Developmental Biology Cancer Virology Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified novel bifunctional molecule multiple melanoma models multiple cancer models histone deacetylase inhibitors elevated h3k27 acetylation comparative structural studies restores anticancer efficacy vdr target genes combining vdr agonism vdr agonist backbone 340 hdaci activity exert anticancer vdr hyperagonist robust bifunctionality rnaseq analysis receptor agonist qpcr revealed likely coupled incorporates hdaci immunomodulatory effects combination therapies coactivator cbp broad array analogs engage active transcription 340 superinduces 340 functions 340 forms |
| status_str | publishedVersion |
| title | Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule |
| title_full | Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule |
| title_fullStr | Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule |
| title_full_unstemmed | Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule |
| title_short | Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule |
| title_sort | Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule |
| topic | Biophysics Biochemistry Medicine Cell Biology Genetics Molecular Biology Pharmacology Developmental Biology Cancer Virology Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified novel bifunctional molecule multiple melanoma models multiple cancer models histone deacetylase inhibitors elevated h3k27 acetylation comparative structural studies restores anticancer efficacy vdr target genes combining vdr agonism vdr agonist backbone 340 hdaci activity exert anticancer vdr hyperagonist robust bifunctionality rnaseq analysis receptor agonist qpcr revealed likely coupled incorporates hdaci immunomodulatory effects combination therapies coactivator cbp broad array analogs engage active transcription 340 superinduces 340 functions 340 forms |