Related Experiment Video

Updated: Jul 20, 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 SHR5428 as a selective and noncovalent inhibitor of CDK7

Minqiang Jia1, Weimin Wang1, Gang Chen1

  • 1R&D Center, Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China.

Bioorganic & Medicinal Chemistry Letters
|August 5, 2023
PubMed

Insights

SHR5428 is a new, selective, noncovalent inhibitor of cyclin-dependent kinase 7 (CDK7). This potent drug candidate shows promise for treating triple-negative breast cancer, demonstrating efficacy in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cyclin-dependent kinase 7 (CDK7) plays a crucial role in regulating cell cycle progression and gene transcription.
  • Dysregulation of CDK7 is implicated in various tumor indications, making it a significant therapeutic target.
  • Targeting CDK7 offers a potential strategy for cancer treatment by modulating both cell cycle and transcription.

Purpose of the Study:

  • To discover and characterize a novel, selective, and noncovalent inhibitor of CDK7.
  • To evaluate the enzymatic activity, cellular potency, and selectivity profile of the identified inhibitor.
  • To assess the pharmacokinetic properties and in vivo efficacy of the novel CDK7 inhibitor in preclinical cancer models.

Main Methods:

  • Enzymatic assays were performed to determine the inhibitory potency of SHR5428 against CDK7.
  • Cellular assays using MDA-MB-468 cells assessed the compound's activity against triple-negative breast cancer.
  • Pharmacokinetic studies were conducted in mouse, rat, and dog models.
  • Selectivity was evaluated against other kinases within the CDK family.
  • In vivo efficacy was tested using a xenograft mouse model derived from HCC70 breast cancer cells.

Main Results:

  • SHR5428 was identified as a potent and selective noncovalent inhibitor of CDK7.
  • The compound exhibited significant cellular activity against triple-negative breast cancer cells (MDA-MB-468).
  • SHR5428 demonstrated favorable pharmacokinetic profiles across preclinical species and high selectivity over other CDKs.
  • Oral administration of SHR5428 resulted in dose-dependent tumor growth inhibition in a breast cancer xenograft model.

Conclusions:

  • SHR5428 is a promising orally efficacious drug candidate targeting CDK7.
  • Its potent enzymatic activity, cellular efficacy, favorable pharmacokinetics, and in vivo antitumor activity support its further development for cancer therapy.
  • The selective inhibition of CDK7 by SHR5428 offers a novel therapeutic approach for triple-negative breast cancer and potentially other malignancies.
Keywords:
CDK7EfficacySARTriple negative breast cancer

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