Related Experiment Video

Updated: Mar 6, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Published on: October 26, 2015

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Development of Dihydroquinoxalinone-Based Dual CDK6/BET Inhibitors for Triple-Negative Breast Cancer Therapy

Long Zheng1, Yiwei Zheng1, Sijie Wu1

  • 1Basic Medical Research Innovation Center for Anti-Cancer Drugs of MOE and Jiangsu Key Laboratory of Bioactive Natural Product Research, China Pharmaceutical University, Nanjing 210009, People's Republic of China.

Journal of Medicinal Chemistry
|March 5, 2026
PubMed

Insights

Researchers developed a novel dual CDK6/BET inhibitor, KWZL-7f15, showing significant promise for treating triple-negative breast cancer (TNBC) by effectively inhibiting cancer cell proliferation and tumor growth in preclinical models.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Pharmacology

Background:

  • Clinical use of CDK4/6 inhibitors for breast cancer is limited by narrow indications.
  • Combination therapies with BET inhibitors are being investigated to enhance efficacy.
  • Triple-negative breast cancer (TNBC) remains a challenging subtype with unmet therapeutic needs.

Purpose of the Study:

  • To design and synthesize novel dual-target inhibitors of CDK6 and BRD4.
  • To evaluate the synergistic effects of CDK4/6 and BET inhibition in TNBC.
  • To identify potent and safe therapeutic agents for TNBC treatment.

Main Methods:

  • Synergistic effect evaluation of Abemaciclib and BQ0 on TNBC cell proliferation in vitro.
  • Design, synthesis, and characterization of dual CDK6/BRD4 inhibitors.
  • In vitro and in vivo evaluation of compound 7f15 in TNBC models (MDA-MB-231 xenograft).
  • Kinase selectivity profiling of 7f15.

Main Results:

  • Abemaciclib and BQ0 showed synergistic inhibition of TNBC cell proliferation.
  • Compounds 7f and 7f15 demonstrated potent dual inhibition of CDK6 and BRD4.
  • 7f15 exhibited significant antitumor activity in a TNBC xenograft model with no major adverse effects.
  • 7f15 was identified as a pan-BET inhibitor.

Conclusions:

  • KWZL-7f15 (7f15) is a novel dual CDK6/BET inhibitor.
  • KWZL-7f15 demonstrates potent antiproliferative and antitumor activity against TNBC.
  • KWZL-7f15 holds significant therapeutic potential for treating triple-negative breast cancer.

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