TY - JOUR
T1 - 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
AU - Boateng, Samuel T.
AU - Roy, Tithi
AU - Agbo, Mercy E.
AU - Mahmud, Md Ashiq
AU - Banang-Mbeumi, Sergette
AU - Chamcheu, Roxane Cherille N.
AU - Yadav, Rajesh K.
AU - Bramwell, Marion
AU - Pham, Long K.
AU - Dang, Danny D.
AU - Jackson, Keith E.
AU - Nagalo, Bolni Marius
AU - Hill, Ronald A.
AU - Efimova, Tatiana
AU - Fotie, Jean
AU - Chamcheu, Jean Christopher
N1 - Publisher Copyright:
© 2023 John Wiley & Sons Ltd.
PY - 2024/1
Y1 - 2024/1
N2 - 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.
AB - 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.
KW - ROCK/Fyn and Hedgehog (Hh) pathway as potential targets
KW - anticancer activity
KW - apoptosis
KW - in silico target(s) prediction
KW - melanoma and nonmelanoma skin cancer cells
UR - http://www.scopus.com/inward/record.url?scp=85179987085&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85179987085&partnerID=8YFLogxK
U2 - 10.1111/cbdd.14418
DO - 10.1111/cbdd.14418
M3 - Article
C2 - 38230791
AN - SCOPUS:85179987085
SN - 1747-0277
VL - 103
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
IS - 1
M1 - e14418
ER -