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In Silico Evaluation of Potential Carcinogenicity of Indole Derivatives as Src Tyrosine Kinases Inhibitors

Src Family Tyrosine Kinase Inhibitors (SFKIs) have been designed as anti-cancer agents in past several years and several small molecules were approved by FDA for clinical studies1. It was shown that various substituted 2-oxindole derivatives have the ability to inhibit several SFKs.2 The discovery of novel small molecules with potential usefulness and design of potent, selective and less toxic anticancer agent is still a major challenge for medicinal chemistry researchers. Unwanted pharmacokinetic (PK) properties and toxicity of drugs are major problems in drug development, therefore predicting ADMET properties and underlying mechanisms of toxicity are of utmost importance for current and future drug discovery. The carcinogenicity potential of 2-oxindole derivates (n=44) that were previously synthesized and tested on tyrosine kinase activitty3 was evaluated in silico by means of ADMET PredictorTM (SimulationsPlus Inc.). The results of this in silico study revealed 2-oxindoles' toxicity expressed as TOX_Risk scores in the range of 0.0 to 3.0 and one or more of the following TOX_Codes were predicted per compound: hERG, rat, HEPX, Xr, Xm and MUT. The carcinogenicity in rat (Xr) was predicted in the range of TD50 2.872 to 37.205 mg/kg/day and carcinogenicity in mouse (Xm) in the range of TD50 17.134 to 1727.808 mg/kg/day. For reference compounds imatinib, PP1, PP2 and for 2-oxindole drug oxyphenisatine (hepatotoxic, withdrawn in 1992), TOX_Risk scores were computed as it follows: 2.757 (hERG, Xr, Xm, HEPX), 1.000 (Xm), 2.00 (Xm, MUT) and 2 (SG, HEPX), respectively. Predicted carcinogenicities Xr and Xm for imatinib were TD50 = 4.998 and 26.696 mg/kg/day, respectively, while Xm for PP1 and PP2, were TD50 5.873 and 6.173 mg/g/day, respectively. For oxyphenisatine Xr and Xm TD50 were 361.92 and 117.71 mg/kg/day, respectively, and the hepatotoxicity was computed as a main TOX_Code. Generally, the majority of investigated 2-oxindoles showed more favorable toxic profiles in comparison to reference compounds. [1] R. Roskoski, Pharmacol. Res., 2015, 94, 9. [2] S. Zhang, D. Yu, Trends Pharmacol. Sci. 2012, 33, 122. [3] Z. Kilic-Kurt, F. Bakar, S. Olgen, Arch. Pharm. Chem. Life Sci. 2015, 348, 1.

Src Tyrosine Kinases Inhibitors ; 2-oxindoles ; ADMET ; Toxicity ; Carcinogenicity ; In Silico Study

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