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Comparison of feline and human immunodeficiency virus reverse transcriptase enzymes through chemical screening and computational analysis
(2024-05-01)
Thammajong, Phanicha
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Aiebchun, Thitinan
;
Boonyarattanakalin, Kanokthip
;
Gleeson, Duangkamol
;
Pobsuk, Nattakarn
Feline immunodeficiency virus (FIV) is a common infection found in domesticated and wild cats worldwide. Despite the wealth of therapeutic understanding of the disease in humans, considerably less information exists regarding the treatment of the disease in felines. Current treatment relies on drugs developed for the related human immunodeficiency virus (HIV) and includes compounds of the popular non-nucleotide reverse transcriptase (NNRTI) class. This is despite FIV-RT being only 67% similar to HIV-1 RT at the enzyme level, increasing to 88% for the allosteric pocket targeted by NNRTIs. The goal of this project was to try to quantify how well the more extensive pharmacological knowledge available for human disease translates to felines. To this end we screened known NNRTIs and 10 diverse pyrimidine analogs identified virtually. We use this chemo-centric probe approach to (a) assess the similarity between the two related RT targets based on the observed experimental inhibition values, (b) try to identify more potent inhibitors at FIV, and (c) gain a better appreciation of the structure–activity relationships (SAR). We found the correlation between IC<inf>50</inf>s at the two targets to be strong (r<sup>2</sup> = 0.87) and identified compound 1 as the most potent inhibitor of FIV with IC<inf>50</inf> of 0.030 μM ± 0.009. This compared to FIV IC<inf>50</inf> values of 0.22 ± 0.17 μM, 0.040 ± 0.010 μM and >160 μM for known anti HIV-1 RT drugs Efavirenz, Rilpivirine, and Nevirapine, respectively. This knowledge, along with an understanding of the structural origin that give rise to any differences could improve the way HIV drugs are repurposed for FIV.
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Sulfonylated Indeno[1,2-c]quinoline Derivatives as Potent EGFR Tyrosine Kinase Inhibitors
(2023-06-06)
Hengphasatporn, Kowit
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Aiebchun, Thitinan
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Mahalapbutr, Panupong
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Auepattanapong, Atima
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Khaikate, Onnicha
The epidermal growth factor receptor (EGFR) has been considered a potential target for lung cancer therapy due to its essential role in regulating the survival and proliferation of cancer cells. Although erlotinib, a potent EGFR tyrosine kinase (EGFR-TK) inhibitor, has been used as the first-line drug for lung cancer treatment, acquired drug resistance caused by the T790M secondary mutation of EGFR-TK inevitably develops after a median response duration of 9-13 months. Thus, the search for promising compounds to effectively target EGFR-TK has become an imperative necessity. In this study, the kinase inhibitory activities of a series of sulfonylated indeno[1,2-c]quinolines (SIQs) against EGFR-TK were experimentally and theoretically investigated. Among the 23 SIQ derivatives studied, eight compounds showed enhanced EGFR-TK inhibitory activity (IC<inf>50</inf> values of ca. 0.6-10.2 nM) compared to the known drug erlotinib (IC<inf>50</inf> of ∼20 nM). In a cell-based assay in human cancer cell lines with EGFR overexpression (A549 and A431 cells), the eight selected SIQs all showed more significant cytotoxicity against A431 than A549 cells, consistent with the higher EGFR expression in A431 cells. Molecular docking and FMO-RIMP2/PCM calculations revealed that SIQ17 occupies the ATP-binding site of EGFR-TK, where its sulfonyl group is mainly stabilized by C797, L718, and E762 residues. Triplicate 500 ns molecular dynamics (MD) simulations also confirmed the binding strength of SIQ17 in complex with EGFR. Overall, the potent SIQ compounds obtained in this work could be further optimized for developing novel anticancer drug candidates targeting EGFR-TK.
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4-Aryl-N-phenylpyrimidin-2-amines targeting EGFR-tyrosine kinase attenuated EGFR-expressing cell lines
(2022-08-01)
Tabtimmai, Lueacha
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Supakun, Prapasri
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Toviwek, Borvornvat
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Jiwacharoenchai, Nattanan
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Kiriwan, Duangnapa
Target therapies have been widely developed to combat various diseases and cancer. Epidermal Growth Factor Receptor is still a currently therapeutic target for solid tumor. Aberration of EGFR activity or expression reflect disease progression and poor prognosis. Recently, several newly synthesized 4-aryl-N-phenylpyrimidin-2-amines with some modifications at R2 selectively elicited cytotoxicity against A549. Therefore, harboring EGFR expression would be reasonable for the assessment. Herein, the 4-aryl-N-phenylpyrimidin-2-amines derivatives; N-(3-{[4-(4-methoxyphenyl) pyrimidin-2-yl]amino}phenyl), 3-{[4-(3-methoxyphenyl) pyrimidin-2-yl] amino}benzene-1-sulfonamide. (13g), methanesulfonamide (13c), 3-[(4-phenylpyrimidin-2-yl)amino] benzene-1-sulfonamide (13f) and 3-(benzene-1-sulfonamide) (5) were selected as promising derivatives for targeted-EGFR analysis. Kinase enzymatic-based assay exhibited IC<inf>50</inf> values of 5.61, 31.92, 73.80 and 0.79 nM of each derivative, respectively whilst 41.50 nM of Gefitinib. Molecular docking deciphered the mode of binding of each derivative in ATP-binding site greater than gefitinib. Although, (13g) demonstrated the highest binding free energy among the other but not in ATP-binding site as the others does that related to its IC<inf>50</inf> values. (13c), (13f), and (5) therefore were subjected for cell-based analysis. A549 and A431 were used as wtEGFR-expressing cells for cell-based assay. (13c), (13f), and (5) had high toxicity towards in both cells while (5) had much more toxicity on A431. (13c), (13f) and (5) not only induced apoptosis in a dose-dependent manner but reduced clonogenic formation greater than gefitinib. Migration of EGF-stimulated A431 was significantly delayed by the compounds over time but they could not delay EGF-stimulated A549 migration. Taken together, (13c), (13f) and (5) would be a newly synthesized derivative by targeting wtEGFR-expressing cells that attenuated EGFR-driven cancer hallmark leading to targeted therapy development.

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