Abstract
Tumorigenesis in humans is a multistep progression that imitates genetic changes leading to cell transformation and malignancy. Oncogenic kinases play a central role in cancer progression, rendering them putative targets for the design of anti-cancer drugs. The presented work aims to identify the potential multi-target inhibitors of oncogenic receptor tyrosine kinases (RTKs) and serine/threonine kinases (STKs). For this, chemoinformatics and structure-based virtual screening approaches were combined with an in vitro validation of lead hits on both cancerous and non-cancerous cell lines. A total of 16 different kinase structures were screened against ~739,000 prefiltered compounds using diversity selection, after which the top hits were filtered for promising pharmacokinetic properties. This led to the identification of 12 and 9 compounds against RTKs and STKs, respectively. Molecular dynamics (MD) simulations were carried out to better comprehend the stability of the predicted hit kinase-compound complexes. Two top-ranked compounds against each kinase class were tested in vitro for cytotoxicity, with compound F34 showing the most promising inhibitory activity in HeLa, HepG2, and Vero cell lines with IC50 values of 145.46 μM, 175.48 μM, and 130.52 μM, respectively. Additional docking of F34 against various RTKs was carried out to support potential multi-target inhibition. Together with reliable MD simulations, these results suggest the promising potential of identified multi-target STK and RTK scaffolds for further kinase-specific anti-cancer drug development toward combinatorial therapies.
Highlights
In humans, tumorigenesis is a multistep process that imitates genetic changes leading toward cell transformation and malignancy [1,2]
We focus on important kinase targets, receptor tyrosine kinases (RTKs) and STKs, involved in a broad range of cancers
We present a systematic, hierarchical structure-based virtual screening (SBVS) workflow to identify kinase inhibitors as anti-cancer compounds with potential multi-target properties
Summary
Tumorigenesis is a multistep process that imitates genetic changes leading toward cell transformation and malignancy [1,2]. Mutations in kinases have been observed in a variety of human tumors, and their deregulation has been shown to be the cause of numerous human malignancies [12,13,14,15,16]. Signal transduction by these kinases activates transcription factors (e.g., AP1, NFκB, Myc), which in turn leads to cell proliferation or the inhibition of programmed cell death by either participating in the deregulation of the cell cycle control or by inhibiting the pro-apoptotic molecules (e.g., Bad, Bax) [6,17,18,19]. Kinases play a central role in oncogenesis and are considered potential targets for anti-cancer drug design [20,21,22,23,24,25,26]
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