Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7.

CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.

Citation

Jason J Marineau, Kristin B Hamman, Shanhu Hu, Sydney Alnemy, Janessa Mihalich, Anzhelika Kabro, Kenneth Matthew Whitmore, Dana K Winter, Stephanie Roy, Stephane Ciblat, Nan Ke, Anneli Savinainen, Ashraf Wilsily, Goran Malojcic, Robert Zahler, Darby Schmidt, Michael J Bradley, Nigel J Waters, Claudio Chuaqui. Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7. Journal of medicinal chemistry. 2022 Jan 27;65(2):1458-1480

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PMID: 34726887

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