Multifaceted approach toward mapping out the anticancer properties of small molecules via in vitro evaluation on melanoma and nonmelanoma skin cancer cells, and in silico target fishing

Samuel T. Boateng, Tithi Roy, Mercy E. Agbo, Md Ashiq Mahmud, Sergette Banang-Mbeumi, Roxane Cherille N. Chamcheu, Rajesh K. Yadav, Marion Bramwell, Long K. Pham, Danny D. Dang, Keith E. Jackson, Bolni Marius Nagalo, Ronald A. Hill, Tatiana Efimova, Jean Fotie*, Jean Christopher Chamcheu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Melanoma and nonmelanoma skin cancers are among the most prevalent and most lethal forms of skin cancers. To identify new lead compounds with potential anticancer properties for further optimization, in vitro assays combined with in-silico target fishing and docking have been used to identify and further map out the antiproliferative and potential mode of action of molecules from a small library of compounds previously prepared in our laboratory. From screening these compounds in vitro against A375, SK-MEL-28, A431, and SCC-12 skin cancer cell lines, 35 displayed antiproliferative activities at the micromolar level, with the majority being primarily potent against the A431 and SCC-12 squamous carcinoma cell lines. The most active compounds 11 (A431: IC50 = 5.0 μM, SCC-12: IC50 = 2.9 μM, SKMEL-28: IC50 = 4.9 μM, A375: IC50 = 6.7 μM) and 13 (A431: IC50 = 5.0 μM, SCC-12: IC50 = 3.3 μM, SKMEL-28: IC50 = 13.8 μM, A375: IC50 = 17.1 μM), significantly and dose-dependently induced apoptosis of SCC-12 and SK-MEL-28 cells, as evidenced by the suppression of Bcl-2 and upregulation of Bax, cleaved caspase-3, caspase-9, and PARP protein expression levels. Both agents significantly reduced scratch wound healing, colony formation, and expression levels of deregulated cancer molecular targets including RSK/Akt/ERK1/2 and S6K1. In silico target prediction and docking studies using the SwissTargetPrediction web-based tool suggested that CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, might be prospective targets for the two most active compounds. Further validation of these targets by western blot analyses, revealed that ROCK/Fyn and its associated Hedgehog (Hh) pathways were downregulated or modulated by the two lead compounds. In aggregate, these results provide a strong framework for further validation of the observed activities and the development of a more comprehensive structure–activity relationship through the preparation and biological evaluation of analogs.

Original languageEnglish (US)
Article numbere14418
JournalChemical Biology and Drug Design
Volume103
Issue number1
DOIs
StatePublished - Jan 2024

Keywords

  • ROCK/Fyn and Hedgehog (Hh) pathway as potential targets
  • anticancer activity
  • apoptosis
  • in silico target(s) prediction
  • melanoma and nonmelanoma skin cancer cells

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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