{"doi":"10.1101/2022.02.28.482167","title":"Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds","abstract":"Abstract Melanoma and non-melanoma skin cancers are the most-lethal and commonest forms of skin cancers, that affecting one-fifth of the US population. With the aim of identifying new lead compounds as starting point for attaining cost-effective therapies, a small library of about 90 molecules was screened in vitro against A375, SKMEL-28, A431, SCC-12 skin cancer cell lines. About 35 of them, mainly dihydroquinolines, C–C and C–N linked biphenyls, and substituted methylgallate or aniline derivatives, displayed low-micromolar range activities, primarily against the A431 and SCC-12 squamous carcinoma cell lines, with only a handful of these compounds displaying any activity against the A375 and SKMEL-28 melanoma cell lines. Compounds 11 (A431: IC 50 = 5.0 µM, SCC-12: IC 50 = 2.9 µM, SKMEL-28: IC 50 = 4.9 µM, A375: IC 50 = 6.7 µM) and 13 (A431: IC 50 = 5.0 µM, SCC-12: IC 50 = 3.3 µM, SKMEL-28: IC 50 = 13.8 µM, A375: IC 50 = 17.1 µM) were the most active across all these cell lines. Furthermore, many of the hit compounds showed little to no activity against mammalian nontumorigenic immortalized HaCaT cells, with a far better selectivity index than cisplatin (a well-known anticancer agent used as a positive control). Compounds 11 and 13 significantly and dose-dependently induced apoptosis of SCC-12 and SK-MEL-28 cells as evidenced by the downregulation of Bcl-2 and upregulation of Bax protein expression levels, and by cleaved caspase-3, caspase-9 and PARP levels. Both agents also significantly reduced scratch wound healing, colony formation, and activated expression levels of major cancer molecular targets such as RSK/AKT/ERK1/2 and S6K1. To provide a better attribute profile for each of the hit molecules, in-silico target(s) prediction, pharmacokinetic and ADMET studies are also reported, together with some preliminary structure-activity relationship outlines. The SwissTargetPrediction web-based tool identified CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, as likely targets for these hit compounds. Furthermore, the SwissADME web_tool predicted these compounds to exhibit high GI tract absorption, good skin permeation, and a viable biodegradability profile. To summarize, these data highlight the promising anticancer potential of these small molecules leads, warranting further investigation and/or optimization towards obtaining clinical candidates for combatting both melanoma and non-melanoma skin cancers.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":299874,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":407624,"name":"Tithi Roy","orcid":"0000-0003-3101-7705","position":1,"is_corresponding":false},{"id":990144,"name":"Mercy E. Agbo","orcid":"0000-0001-5249-3474","position":2,"is_corresponding":false},{"id":990482,"name":"Sergette Banang‐Mbeumi","orcid":null,"position":3,"is_corresponding":false},{"id":990483,"name":"Roxane‐Cherille N. Chamcheu","orcid":null,"position":4,"is_corresponding":false},{"id":990484,"name":"Marion Bramwell","orcid":null,"position":5,"is_corresponding":false},{"id":90371,"name":"Long Pham","orcid":"0000-0003-4117-8860","position":6,"is_corresponding":false},{"id":407625,"name":"Keith E. Jackson","orcid":"0000-0002-4962-1735","position":7,"is_corresponding":false},{"id":373499,"name":"Ronald A. Hill","orcid":"0000-0003-4622-5996","position":8,"is_corresponding":false},{"id":417558,"name":"Bolni Marius Nagalo","orcid":"0000-0002-2173-7912","position":9,"is_corresponding":false},{"id":990145,"name":"Tatiana Efimova","orcid":"0000-0002-9869-1545","position":10,"is_corresponding":false},{"id":990146,"name":"Jean Fotie","orcid":"0000-0002-3404-4533","position":11,"is_corresponding":false},{"id":373502,"name":"Jean Christopher Chamcheu","orcid":"0000-0002-3927-5664","position":12,"is_corresponding":false},{"id":990143,"name":"Samuel Boateng","orcid":"0000-0002-0307-3286","position":0,"is_corresponding":true}],"reference_count":112,"raw_metadata":null,"created_at":"2026-07-19T00:31:49.412501Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}