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Targeting RECQL5 Functions, by a Small Molecule, Selectively Kills Breast Cancer in Vitro and in Vivo
Saikat Chakraborty1,2, Kartik Dutta1,2, Pooja Gupta1,2
1Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
Abstract:
Clinical and preclinical data reveal that RECQL5 protein overexpression in breast cancer was strongly correlated with poor prognosis, survival, and therapeutic resistance. In the current investigation, we report design, synthesis, and specificity of a small molecule, 4a, which can preferentially kill RECQL5-expressing breast cancers but not RECQL5 knockout. Our stringent analysis showed that compound 4a specifically sensitizes RECQL5-expressing cancers, while it did not have any effect on other members of DNA RECQL-helicases. Integrated approaches of organic synthesis, biochemical, in silico molecular simulation, knockouts, functional mutation, and rescue experiments showed that 4a potently inhibits RECQL5-helicase activity and stabilizes RECQL5-RAD51 physical interaction, leading to impaired HRR and preferential killing of RECQL5-expressing breast cancer. Moreover, 4a treatment led to the efficient sensitization of cisplatin-resistant breast cancers but not normal mammary epithelial cells. Pharmacologically, compound 4a was orally effective in reducing the growth of RECQL5-expressing breast tumors (human xenograft) in NUDE-mice with no appreciable toxicity to the vital organs.
Insights
A new small molecule, 4a, selectively targets and kills breast cancers overexpressing RECQL5 protein. This compound offers a promising therapeutic strategy for improving outcomes in RECQL5-positive breast cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RECQL5 protein overexpression in breast cancer correlates with poor prognosis, survival, and therapeutic resistance.
- Targeting RECQL5 presents a potential strategy for novel breast cancer therapies.
Purpose of the Study:
- To design, synthesize, and characterize a small molecule (compound 4a) that selectively targets and eliminates RECQL5-expressing breast cancer cells.
- To investigate the mechanism of action and therapeutic efficacy of compound 4a in preclinical models.
Main Methods:
- Organic synthesis, biochemical assays, in silico molecular simulation.
- Gene knockout, functional mutation, and rescue experiments.
- In vivo studies using human xenograft models in NUDE mice.
Main Results:
- Compound 4a preferentially kills RECQL5-expressing breast cancers, sparing RECQL5 knockout cells and other DNA RECQL helicases.
- 4a inhibits RECQL5 helicase activity, stabilizes RECQL5-RAD51 interaction, impairs homologous recombination repair (HRR), and induces cancer cell death.
- 4a sensitizes cisplatin-resistant breast cancers and shows oral efficacy in reducing tumor growth without significant toxicity.
Conclusions:
- Compound 4a is a potent and specific inhibitor of RECQL5, demonstrating significant therapeutic potential for RECQL5-positive and cisplatin-resistant breast cancers.
- 4a represents a promising orally bioavailable drug candidate with a favorable safety profile for treating aggressive breast cancer subtypes.
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