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Ribociclib derivative Rib-CA suppresses breast cancer progression via p53-dependent apoptosis

Mengwei Song1, Ying Zhou1, Xudong Yu1

  • 1Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, PR China.

Toxicology and Applied Pharmacology
|July 17, 2025
PubMed

Insights

A new Ribociclib derivative, Rib-CA, shows enhanced antitumor and anti-metastatic effects against breast cancer by activating p53 signaling and suppressing tumor growth. This novel compound demonstrates significant therapeutic potential for breast cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Breast cancer presents a significant global health burden, with drug resistance to existing therapies like CDK4/6 inhibitors being a major challenge.
  • Ribociclib, a CDK4/6 inhibitor, offers clinical benefits but faces limitations due to acquired drug resistance.

Purpose of the Study:

  • To design and synthesize a novel Ribociclib derivative, Rib-CA, with potentially enhanced efficacy.
  • To evaluate the antitumor and anti-metastatic effects of Rib-CA in vitro and in vivo.
  • To elucidate the underlying molecular mechanisms and identify potential biomarkers for Rib-CA activity.

Main Methods:

  • In vitro assays included MTT, colony formation, EdU incorporation, cell adhesion, Transwell invasion, and wound healing.
  • In vivo evaluations utilized the chick chorioallantoic membrane (CAM) assay and xenograft models.
  • Mechanism of action was explored through transcriptomics, Western blotting, machine learning, and ADMETlab 2.0 for pharmacokinetics and safety.

Main Results:

  • Rib-CA demonstrated superior anti-proliferative and anti-metastatic activity compared to Ribociclib in MDA-MB-231 and MCF-7 breast cancer cells.
  • The compound activated p53 signaling, induced apoptosis, and caused G2/M cell cycle arrest.
  • In vivo studies showed Rib-CA more effectively suppressed tumor growth and angiogenesis than Ribociclib, with favorable pharmacokinetic properties.

Conclusions:

  • Rib-CA exhibits enhanced antitumor activity and metastasis suppression in breast cancer models, mediated by p53 pathway activation.
  • Identified potential biomarkers CACHD1 and LAGE3 are linked to p53 signaling and immune regulation.
  • Rib-CA represents a promising therapeutic candidate for breast cancer treatment, potentially overcoming resistance mechanisms.
Keywords:
Breast cancerRNA-SeqRib-CAapoptosisp53

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