Discovery of AZD8421: A Potent CDK2 Inhibitor with Selectivity Against Other CDK Family Members and the Human Kinome
Avipsa Ghosh, Afshan Ahmed, Konstantina Amoiradaki, Amber Balazs, Bernard Barlaam, Michael S. Bodnarchuk, Gavin W. Collie, Ian L. Dale, Christopher R. Denz, Lisa Drew, Scott D. Edmondson, Jun Fan, Stephen E. Fawell, Frederick W. Goldberg, Ariamala Gopalsamy, Michael Grondine, Grace Chun Guo, Sudhir M. Hande, Holia Hatoum‐Mokdad, Alexander W. Hird, Rachel Howells, Jessie Hao-Ru Hsu, Jessica J. R. Hudson, Anne Jackson, Michelle L. Lamb, Gillian M. Lamont, Scott G. Lamont, Phillip A. Lichtor, Lisa McWilliams, David Milne, Scott N. Mlynarski, Priyanka Narasimhan, Matthew F. Peters, A. Pflug, Hannah Pollard, Mei Qin, Corinne Reimer, Kevin J. Robbins, James Robinson, Sha Li, Hongyao She, James E. Sheppeck, Baljinder Singh, Kun Song, Qibin Su, Reem Telmesani, Scott Throner, Christina Vasalou, Lei Wang, Yanjun Wang, David M. Wilson, Poppy Winlow, Wenzhan Yang, Tieguang Yao, Yun Zhang, Zirong Zhang, Diana Zindel, Jeffrey W. Johannes
Abstract
Targeting CDK2 with first generation CDK2 inhibitors suffered from a reduced therapeutic index likely due to toxicity stemming from lack of selectivity against the CDK family and other kinases. Recently, CDK2 has been identified as a mediator of resistance to CDK4/6 inhibitors in the context of high levels of cyclin E expression. Discovery of highly selective CDK2 inhibitors may minimize off-target effects, reduce toxicity observed with first generation CDK2 inhibitors, and allow precise targeting of aberrant cell cycle progression and resistance mechanisms mediated by high cyclin E/CDK2 activity. To this end, we report the discovery of AZD8421, a potent and highly selective CDK2 inhibitor, which exhibits superior selectivity for CDK2 over CDK1, other CDK family members, and the broader human kinome. AZD8421 demonstrates favorable pharmacokinetic properties, including excellent solubility and robust in vitro stability. Demonstrated efficacy in an ovarian cancer patient-derived xenograft model further supports its potential as a therapeutic agent.