Authors: Samuel Boateng | Tithi Roy | Mercy E. Agbo | Sergette Banang‐Mbeumi | Roxane‐Cherille N. Chamcheu | Marion Bramwell | Long Pham | Keith E. Jackson | Ronald A. Hill | Bolni Marius Nagalo | Tatiana Efimova | Jean Fotie | Jean Christopher Chamcheu
Source: bioRxiv (Cold Spring Harbor Laboratory) (preprint, 2022-03-02)
Field: Chemistry — Organic Chemistry

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 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. HaCaT ; Cell culture ; Apoptosis ; Melanoma ; Downregulation and upregulation ; Cancer research ; Cancer ; Population ; Cisplatin ; A431 cells ; Caspase 7 ; Biology ; Cancer cell ; Cell ; Chemistry ; Caspase 3 ; Cell cycle ; Medicine ; Biochemistry ; Programmed cell death ; Molecular medicine ; Genetics Synthesis and biological activity ; Microbial Natural Products and Biosynthesis ; Computational Drug Discovery Methods