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

  • J Med Chem. 2022 Jan 27;65(2):1458-1480. doi: 10.1021/acs.jmedchem.1c01171.
Jason J Marineau  1 ,  Kristin B Hamman  1 ,  Shanhu Hu  1 ,  Sydney Alnemy  1 ,  Janessa Mihalich  1 ,  Anzhelika Kabro  2 ,  Kenneth Matthew Whitmore  2 ,  Dana K Winter  2 ,  Stephanie Roy  2 ,  Stephane Ciblat  2 ,  Nan Ke  1 ,  Anneli Savinainen  1 ,  Ashraf Wilsily  1 ,  Goran Malojcic  1 ,  Robert Zahler  1 ,  Darby Schmidt  1 ,  Michael J Bradley  1 ,  Nigel J Waters  1 ,  Claudio Chuaqui  1
Affiliations
  • 1. Syros Pharmaceuticals Inc., 35 Cambridge Park Drive, Fourth Floor, Cambridge, Massachusetts 02140, United States.
  • 2. Paraza Pharma Inc., 2525 Avenue Marie-Curie, Montreal, Quebec H4S 2E1, Canada.
PMID: 34726887 DOI: 10.1021/acs.jmedchem.1c01171
Abstract

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.

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