In Silico‐Enabled Discovery and Development of Potent and Selective CDK11 Inhibitors

In Silico‐Enabled Discovery and Development of Potent and Selective CDK11 Inhibitors

ChemMedChem

10.1002/cmdc.202500882

https://doi.org/10.1002/cmdc.202500882

Frankie S. Mak, Fui Mee Ng, Padmanabhan Anbazhagan, Vikas Madan, Qian Wen Tan, Yiyang See, Diane Lim, Frances Karla Kusuma, Hannah Toh, Juliana Mohammad, Haiyan Yang, Sandra Sim, Li Hong Tan, Eileen Tay, Ronald Toh Kuan Hai, Perlyn Zekui Kwek, Mei Yee Wong, Deepika Raman, Qi An Ang, Vithya Manoharan, Susmitha Vuddagiri, Monique Danielle Dawson, Alison Tan, Joma Kanikadu Joy, Bong Hwa Gan, Choon Bing Low, Haoying Xu, Siew Pheng Lim, Hannes Hentze, Joseph Cherian, Chong Teik Tan, Jackie Ang, Kantharaj Ethirajulu, Klement Foo, Inderjeet Singh, Weijun Xu

CDK11 inhibitors, molecular dynamic simulations, structure-based drug design, virtual screen

26 March 2026

Mak, F. S., Ng, F. M., Anbazhagan, P., Madan, V., Tan, Q. W., See, Y., Lim, D., Kusuma, F. K., Toh, H., Mohammad, J., Yang, H., Sim, S., Tan, L. H., Tay, E., Hai, R. T. K., Kwek, P. Z., Wong, M. Y., Raman, D., Ang, Q. A., et al. (2026). In Silico‐Enabled Discovery and Development of Potent and Selective CDK11 Inhibitors. ChemMedChem, 21(6). Portico. https://doi.org/10.1002/cmdc.202500882

Cyclin-dependent kinase 11 (CDK11) plays a critical role in cell cycle regulation and transcriptional control, making it a promising target for therapeutic intervention in cancer and other proliferative disorders. This study employs computationally driven approaches encompassing homology modeling, molecular dynamic simulations, ultra-large scale virtual screening and medicinal chemistry optimization to develop a series of novel inhibitors of CDK11. Our virtual screening pipeline led to the identification of two initial hits (compounds 3 and 4), which were further evaluated through structure-activity relationship (SAR) studies. Together with structure-guided molecular docking and design, these SAR analyses revealed key structural motifs and functional groups that are crucial for inhibitory activity and selectivity, providing insights into the efficient hit-to-lead optimization. Compound 37 emerged as an optimized potent and selective CDK11 inhibitor (IC50 4nM, kinome panel clean). In a lung tumour model, mice dosed twice with 100 mg/kg compound 37 showed ~ 30% tumour growth inhibition (TGI). Both in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo mouse pharmacokinetics (PK) profiling show that compound 37 possesses excellent pharmaco-kinetic/dynamic properties, positioning the compound for further development and evaluation as lead candidate for CDK11 targeted therapy. The findings from this study contribute to the development of novel chemotypes for CDK11-targeted therapies and offer a framework for future drug discovery efforts aimed at modulating CDK11 activity. The series of compounds developed throughout this study represent novel tools for aiding the mechanism of CDK11 mediated pathophysiology. The integration of in silico modeling, screening and structure-based drug design provides a robust strategy for accelerating the identification of potent and selective inhibitors for other CDK families.

Publisher Copyright

This research is supported by core funding from: Experimental Drug Development Centre (EDDC)
Grant Reference no. :

This is the peer reviewed version of the following article: Mak, F. S., Ng, F. M., Anbazhagan, P., Madan, V., Tan, Q. W., See, Y., Lim, D., Kusuma, F. K., Toh, H., Mohammad, J., Yang, H., Sim, S., Tan, L. H., Tay, E., Hai, R. T. K., Kwek, P. Z., Wong, M. Y., Raman, D., Ang, Q. A., et al. (2026). In Silico‐Enabled Discovery and Development of Potent and Selective CDK11 Inhibitors. ChemMedChem, 21(6). Portico. https://doi.org/10.1002/cmdc.202500882 , which has been published in final form at https://doi.org/10.1002/cmdc.202500882. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.

https://oar.a-star.edu.sg/communities-collections/articles/23445

1860-7179
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Experimental Drug Development Centre