Targeting RECQL5 Functions, by a Small Molecule, Selectively Kills Breast Cancer in Vitr o and in Vivo

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, , which can preferentially kill...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-02, Vol.64 (3), p.1524-1544
Main Authors: Chakraborty, Saikat, Dutta, Kartik, Gupta, Pooja, Das, Anubrata, Das, Amit, Ghosh, Sunil Kumar, Patro, Birija Sankar
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Antineoplastic Agents - toxicity
Breast Neoplasms - drug therapy
Cell Cycle - drug effects
Cell Line, Tumor
Cisplatin - pharmacology
Computer Simulation
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Female
Gene Expression Regulation, Neoplastic - drug effects
Gene Knockout Techniques
Humans
Mice
Mice, Inbred C57BL
Mice, Nude
Models, Molecular
RecQ Helicases - drug effects
RecQ Helicases - genetics
Xenograft Model Antitumor Assays
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Summary: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, , which can preferentially kill RECQL5-expressing breast cancers but not RECQL5 knockout. Our stringent analysis showed that compound 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, molecular simulation, knockouts, functional mutation, and rescue experiments showed that potently inhibits RECQL5-helicase activity and stabilizes RECQL5-RAD51 physical interaction, leading to impaired HRR and preferential killing of RECQL5-expressing breast cancer. Moreover, treatment led to the efficient sensitization of cisplatin-resistant breast cancers but not normal mammary epithelial cells. Pharmacologically, compound 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c01692