Related Experiment Video

Updated: Oct 14, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

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

Jason J Marineau1, Kristin B Hamman1, Shanhu Hu1

  • 1Syros Pharmaceuticals Inc., 35 Cambridge Park Drive, Fourth Floor, Cambridge, Massachusetts 02140, United States.

Journal of Medicinal Chemistry
|November 2, 2021
PubMed

Insights

A new drug, SY-5609, is a potent and selective inhibitor of cyclin-dependent kinase 7 (CDK7). It shows promise in preclinical cancer models and has entered clinical trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cyclin-dependent kinase 7 (CDK7) plays a crucial role in cell cycle regulation and transcription.
  • Dysregulation of CDK7 is implicated in various cancers, making it a significant therapeutic target.

Purpose of the Study:

  • To describe the discovery and preclinical development of SY-5609, a novel CDK7 inhibitor.
  • To evaluate the potency, selectivity, and in vivo efficacy of SY-5609.

Main Methods:

  • Structure-based drug design was employed to achieve high selectivity and potency.
  • In vitro biochemical assays determined CDK7 inhibition and selectivity.
  • Cellular assays assessed CDK7 inhibition and metabolic stability.
  • In vivo efficacy was evaluated in mouse xenograft models.

Main Results:

  • SY-5609 demonstrated sub-nanomolar binding affinity (Kd) for CDK7.
  • High selectivity was achieved, with >4000-fold selectivity over the closest off-target.
  • SY-5609 showed potent CDK7 inhibition in cellular assays.
  • Significant efficacy was observed in mouse xenograft models at doses as low as 2 mg/kg.
  • The drug candidate exhibited favorable metabolic stability.

Conclusions:

  • SY-5609 is a potent, selective, and orally available CDK7 inhibitor.
  • Its favorable preclinical profile supports its clinical development for cancer therapy.
  • SY-5609 represents a promising therapeutic candidate targeting CDK7 in oncology.

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