MC180295 is a highly potent and selective CDK9 inhibitor with preclinical in vitro and in vivo efficacy in cancer
Abstract Background Inhibition of cyclin-dependent kinase 9 (CDK9), a novel epigenetic target in cancer, can reactivate epigenetically silenced genes in cancer by dephosphorylating the SWI/SNF chromatin remodeler BRG1. Here, we characterized the anti-tumor efficacy of MC180295, a newly developed CDK...
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Clinical Epigenetics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13148-023-01617-3 |
| _version_ | 1797363184742432768 |
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| author | Hanghang Zhang Chen Huang John Gordon Sijia Yu George Morton Wayne Childers Magid Abou-Gharbia Yi Zhang Jaroslav Jelinek Jean-Pierre J. Issa |
| author_facet | Hanghang Zhang Chen Huang John Gordon Sijia Yu George Morton Wayne Childers Magid Abou-Gharbia Yi Zhang Jaroslav Jelinek Jean-Pierre J. Issa |
| author_sort | Hanghang Zhang |
| collection | DOAJ |
| description | Abstract Background Inhibition of cyclin-dependent kinase 9 (CDK9), a novel epigenetic target in cancer, can reactivate epigenetically silenced genes in cancer by dephosphorylating the SWI/SNF chromatin remodeler BRG1. Here, we characterized the anti-tumor efficacy of MC180295, a newly developed CDK9 inhibitor. Methods In this study, we explored the pharmacokinetics of MC180295 in mice and rats, and tested the anti-tumor efficacy of MC180295, and its enantiomers, in multiple cancer cell lines and mouse models. We also combined CDK9 inhibition with a DNA methyltransferase (DNMT) inhibitor, decitabine, in multiple mouse models, and tested MC180295 dependence on T cells. Drug toxicity was measured by checking body weights and complete blood counts. Results MC180295 had high specificity for CDK9 and high potency against multiple neoplastic cell lines (median IC50 of 171 nM in 46 cell lines representing 6 different malignancies), with the highest potency seen in AML cell lines derived from patients with MLL translocations. MC180295 is a racemic mixture of two enantiomers, MC180379 and MC180380, with MC180380 showing higher potency in a live-cell epigenetic assay. Both MC180295 and MC180380 showed efficacy in in vivo AML and colon cancer xenograft models, and significant synergy with decitabine in both cancer models. Lastly, we found that CDK9 inhibition-mediated anti-tumoral effects were partially dependent on CD8 + T cells in vivo, indicating a significant immune component to the response. Conclusions MC180380, an inhibitor of cyclin-dependent kinase 9 (CDK9), is an efficacious anti-cancer agent worth advancing further toward clinical use. |
| first_indexed | 2024-03-08T16:17:27Z |
| format | Article |
| id | doaj.art-892c78200eb14c6280a512cb5e5194fd |
| institution | Directory Open Access Journal |
| issn | 1868-7083 |
| language | English |
| last_indexed | 2024-03-08T16:17:27Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj.art-892c78200eb14c6280a512cb5e5194fd2024-01-07T12:31:18ZengBMCClinical Epigenetics1868-70832024-01-0116111410.1186/s13148-023-01617-3MC180295 is a highly potent and selective CDK9 inhibitor with preclinical in vitro and in vivo efficacy in cancerHanghang Zhang0Chen Huang1John Gordon2Sijia Yu3George Morton4Wayne Childers5Magid Abou-Gharbia6Yi Zhang7Jaroslav Jelinek8Jean-Pierre J. Issa9Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple UniversityFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple UniversityMoulder Center for Drug Discovery Research, Temple University School of PharmacyFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple UniversityMoulder Center for Drug Discovery Research, Temple University School of PharmacyMoulder Center for Drug Discovery Research, Temple University School of PharmacyMoulder Center for Drug Discovery Research, Temple University School of PharmacyFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple UniversityFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple UniversityFels Institute for Cancer Research, Lewis Katz School of Medicine at Temple UniversityAbstract Background Inhibition of cyclin-dependent kinase 9 (CDK9), a novel epigenetic target in cancer, can reactivate epigenetically silenced genes in cancer by dephosphorylating the SWI/SNF chromatin remodeler BRG1. Here, we characterized the anti-tumor efficacy of MC180295, a newly developed CDK9 inhibitor. Methods In this study, we explored the pharmacokinetics of MC180295 in mice and rats, and tested the anti-tumor efficacy of MC180295, and its enantiomers, in multiple cancer cell lines and mouse models. We also combined CDK9 inhibition with a DNA methyltransferase (DNMT) inhibitor, decitabine, in multiple mouse models, and tested MC180295 dependence on T cells. Drug toxicity was measured by checking body weights and complete blood counts. Results MC180295 had high specificity for CDK9 and high potency against multiple neoplastic cell lines (median IC50 of 171 nM in 46 cell lines representing 6 different malignancies), with the highest potency seen in AML cell lines derived from patients with MLL translocations. MC180295 is a racemic mixture of two enantiomers, MC180379 and MC180380, with MC180380 showing higher potency in a live-cell epigenetic assay. Both MC180295 and MC180380 showed efficacy in in vivo AML and colon cancer xenograft models, and significant synergy with decitabine in both cancer models. Lastly, we found that CDK9 inhibition-mediated anti-tumoral effects were partially dependent on CD8 + T cells in vivo, indicating a significant immune component to the response. Conclusions MC180380, an inhibitor of cyclin-dependent kinase 9 (CDK9), is an efficacious anti-cancer agent worth advancing further toward clinical use.https://doi.org/10.1186/s13148-023-01617-3Epigenetic therapyCDK9ImmunosensitizationMC180380Anti-tumoral effects |
| spellingShingle | Hanghang Zhang Chen Huang John Gordon Sijia Yu George Morton Wayne Childers Magid Abou-Gharbia Yi Zhang Jaroslav Jelinek Jean-Pierre J. Issa MC180295 is a highly potent and selective CDK9 inhibitor with preclinical in vitro and in vivo efficacy in cancer Clinical Epigenetics Epigenetic therapy CDK9 Immunosensitization MC180380 Anti-tumoral effects |
| title | MC180295 is a highly potent and selective CDK9 inhibitor with preclinical in vitro and in vivo efficacy in cancer |
| title_full | MC180295 is a highly potent and selective CDK9 inhibitor with preclinical in vitro and in vivo efficacy in cancer |
| title_fullStr | MC180295 is a highly potent and selective CDK9 inhibitor with preclinical in vitro and in vivo efficacy in cancer |
| title_full_unstemmed | MC180295 is a highly potent and selective CDK9 inhibitor with preclinical in vitro and in vivo efficacy in cancer |
| title_short | MC180295 is a highly potent and selective CDK9 inhibitor with preclinical in vitro and in vivo efficacy in cancer |
| title_sort | mc180295 is a highly potent and selective cdk9 inhibitor with preclinical in vitro and in vivo efficacy in cancer |
| topic | Epigenetic therapy CDK9 Immunosensitization MC180380 Anti-tumoral effects |
| url | https://doi.org/10.1186/s13148-023-01617-3 |
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