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Discovery of rigid linker-based CDK4/6 PROTACs for the treatment of breast cancer

Guoyong Pan1, You Li1, Jinke Tan1

  • 1State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory of Targetome and innovative Drugs Medicines, China Pharmaceutical University, Nanjing 211198, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.

Bioorganic Chemistry
|August 21, 2026
PubMed

Insights

New PROTACs targeting CDK4/6, like compound P11, show promise in degrading cancer proteins and overcoming resistance in breast cancer treatment. This offers a potential new strategy beyond traditional inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Selective cyclin-dependent kinase (CDK) 4/6 inhibitors are key in breast cancer therapy.
  • Acquired resistance limits the long-term efficacy of CDK4/6 inhibitors.
  • Proteolysis-targeting chimera (PROTAC) technology offers a novel approach to overcome drug resistance.

Purpose of the Study:

  • To design and synthesize novel CDK4/6 PROTACs based on dalpiciclib.
  • To evaluate the efficacy of these PROTACs in preclinical models of breast cancer.
  • To assess the potential of PROTACs to overcome acquired resistance to CDK4/6 inhibitors.

Main Methods:

  • Synthesis of novel CDK4/6 PROTACs incorporating rigid linkers.
  • Assessment of CDK4/6 degradation activity via the ubiquitin-proteasome system.
  • In vitro studies on breast cancer cell lines (proliferation, colony formation, cell cycle arrest).
  • In vivo efficacy evaluation in an MCF-7 xenograft mouse model.

Main Results:

  • The optimal compound P11 demonstrated potent and selective CDK4/6 degradation.
  • P11 formed a stable ternary complex with CDK6 and CRBN.
  • P11 inhibited breast cancer cell proliferation, colony formation, and induced cell cycle arrest.
  • P11 suppressed tumor growth in vivo, outperforming dalpiciclib.
  • P11 showed potential in overcoming acquired resistance to CDK4/6 inhibitors.

Conclusions:

  • Novel CDK4/6 PROTACs, exemplified by P11, are effective in degrading target proteins.
  • P11 exhibits significant anti-breast cancer activity in vitro and in vivo.
  • P11 represents a promising preclinical candidate for overcoming resistance to CDK4/6 inhibitors in breast cancer therapy.
Keywords:
CDK4/6Cell cycleDegradationPROTACResistance

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