Structure-Based Discovery of HS34: A Highly Selective and Orally Bioavailable CDK9 Inhibitor for Triple-Negative
Yaoguang Huang1, Wenwu Liu2, Xiaoyu Shi1
1School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
Abstract:
Triple-negative breast cancer (TNBC) is a highly aggressive subtype that lacks effective targeted therapies and exhibits strong dependence on CDK9-driven transcription. Here, we report a structure-based drug design strategy exploiting CDK9-specific conformations to discover a novel series of potent inhibitors. This approach yielded HS34, a coumarin-based CDK9 inhibitor with low-nanomolar potency and exceptional selectivity. In cellular assays, HS34 displayed potent antiproliferative activity against TNBC cells, outperforming the reference inhibitor KB-0742. Mechanistically, HS34 suppresses RNAP II Ser2 phosphorylation, leading to the downregulation of short-lived survival and oncogenic proteins such as Mcl-1 and c-Myc, and consequently inducing apoptosis and blocking EMT-associated invasion. Furthermore, HS34 exhibits favorable DMPK properties, including high oral bioavailability and metabolic stability, which align with the significant antitumor efficacy observed in an orally treated xenograft model. Collectively, these findings establish HS34 as a selective CDK9 inhibitor and demonstrate that exploiting target-specific conformational features offers an effective strategy for kinase selectivity.
Insights
A new drug, HS34, effectively targets CDK9 in triple-negative breast cancer (TNBC) by inhibiting transcription. This selective CDK9 inhibitor shows potent anti-cancer activity and favorable drug properties, offering a promising new therapeutic strategy for TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies.
- TNBC is highly dependent on Cyclin-Dependent Kinase 9 (CDK9) for transcription.
Purpose of the Study:
- To discover novel, potent, and selective CDK9 inhibitors for TNBC treatment.
- To explore a structure-based drug design strategy targeting CDK9-specific conformations.
Main Methods:
- Structure-based drug design was employed to identify inhibitors.
- HS34, a coumarin-based compound, was synthesized and characterized.
- Cellular assays, mechanistic studies, and xenograft models were used to evaluate HS34 efficacy.
Main Results:
- HS34 demonstrated low-nanomolar potency and high selectivity for CDK9.
- HS34 exhibited potent antiproliferative activity against TNBC cells, surpassing KB-0742.
- HS34 suppressed RNAP II phosphorylation, downregulated Mcl-1 and c-Myc, induced apoptosis, and blocked invasion.
- HS34 showed favorable DMPK properties and significant antitumor efficacy in vivo.
Conclusions:
- HS34 is a potent and selective CDK9 inhibitor with therapeutic potential for TNBC.
- Exploiting target-specific conformational features is an effective strategy for kinase inhibitor design.
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