How to cite this paper
Abouelenein, M., Elsersy, Y., Salam, H., Awad, H., El-Shahid, Z., Abdel-Aal, M & Abo-Salem, H. (2025). Indole–1,2,4-triazole hybrids as selective ERK inhibitors: Synthesis, anticancer evaluation, and molecular modeling.Current Chemistry Letters, 14(4), 851-866.
Refrences
1 Kumar D., Sharma P., Singh H., Nepali K., Gupta G. K., Jain S. K., Ntie-Kang F. (2017) The value of pyrans as anticancer scaffolds in medicinal chemistry. RSC Advances, 7, 36977–36999. https://doi.org/10.1039/C7RA05441F.
2 Kumar A., Jaitak V. (2019) Natural products as multidrug resistance modulators in cancer. Eur. J. Med. Chem., 176, 268–291. https://doi.org/10.1016/j.ejmech.2019.05.027.
3 Ferlay J., Colombet M., Soerjomataram I., Parkin D. M., Piñeros M., Znaor A., Bray F. (2021) Cancer statistics for the year 2020: An overview. Int. J. Cancer., 149, 778–789. https://doi.org/10.1002/ijc.33588.
4 Sung H., Ferlay J., Siegel R. L., Laversanne M., Soerjomataram I., Jemal A., Bray F. (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 71, 209–249. https://doi.org/10.3322/caac.21660.
5 Liu B., Zhou H., Tan L., Siu K. T. H., Guan X.-Y. (2024) Exploring treatment options in cancer: Tumor treatment strategies. Signal Transduct.Target Ther., 9, 175. https://doi.org/10.1038/s41392-024-01856-7.
6 Punekar S. R., Velcheti V., Neel B. G., Wong K.-K. (2022) The current state of the art and future trends in RAS-targeted cancer therapies. Nat. Rev. Clin. Oncol., 19, 637–655. https://doi.org/10.1038/s41571-022-00671-9.
7 Boshta N. M., Temirak A., El-Shahid Z. A., Shafiq Z., Soliman A. A. F. (2024) Design, synthesis, molecular docking and biological evaluation of 1,3,5-trisubstituted-1H-pyrazole derivatives as anticancer agents with cell cycle arrest, ERK and RIPK3-kinase activities. Bioorg. Chem., 143, 107058. https://doi.org/10.1016/j.bioorg.2023.107058
8 Vališ K., Novák, P. (2020) Targeting ERK–Hippo interplay in cancer therapy. Int. J. Mol. Sci., 21, 3236. https://doi.org/10.3390/ijms21093236.
9 Zhong L., Li Y., Xiong L., Wang W., Wu M., Yuan T., Yang W., Tian C., Miao Z., Wang T., Yang S. (2021) Small molecules in targeted cancer therapy: Advances, challenges, and future perspectives. Signal Transduct. Target Ther., 6, 201. https://doi.org/10.1038/s41392-021-00572-w.
10 Sebaiy M. M., El-Adl S. M., Nafea A., Mattar A. A., Abdul-Malik M. A., Abdel-Raheem S. A., Elbaramawi S. S. (2024) Review: Instrumental Analytical techniques for Evaluating some Anti-infective Drugs in Pharmaceutical Products and Biological Fluids. Curr. Chem. Lett., 13(3), 491-502.
11 Abdel-Megid M., Salem M. E., El-boghdady A. H., El-Rashedy A. A., Abdel-Aal M. T., Nassrallah A., Aboelnaga A., Abouelenein M. G. (2025) Novel Pyrano [2, 3-c] pyrazole Derivatives: Synthesis, Spectroscopic Characterization, and In Silico Evaluation of Interactions with VEGFR-1 and Aromatase. J. Mol. Struct., 143107. https://doi.org/10.1016/j.molstruc.2025.143107
12 Philoppes J. N., Abdelgawad M. A., Abourehab M. A. S., Sebak M., Darwish M. A., Lamie P. F. (2023) Novel N-methylsulfonyl-indole derivatives: Biological activity and COX-2/5-LOX inhibitory effect with improved gastro protective profile and reduced cardiovascular risks. J. Enzyme Inhib. Med. Chem., 38, 246–266. https://doi.org/10.1080/14756366.2022.2145283.
13 Salerno S., Barresi E., Baglini E., Poggetti V., Da Settimo F.,Taliani S. (2023) Target-based anticancer indole derivatives for the development of anti-glioblastoma agents. Molecules, 28, 2587. https://doi.org/10.3390/molecules28062587.
14 Luo M.-L., Huang W., Zhu H.-P., Peng C., Zhao Q., Han B. (2022) Advances in indole-containing alkaloids as potential anticancer agents by regulating autophagy. Biomed. Pharmacother., 149, 112827. https://doi.org/10.1016/j.biopha.2022.112827.
15 Jia Z., Zhang Z., Tian Q., Wu H., Xie Y., Li A., Zhang H., Yang Z., Zhang X. (2021) Integration of transcriptomics and metabolomics reveals anlotinib-induced cytotoxicity in colon cancer cells. Gene., 786, 145625. https://doi.org/10.1016/j.gene.2021.145625.
16 Lu J., Zhong H., Chu T., Zhang X., Li R., Sun J., Zhong R., Yang Y., Alam M. S., Lou Y., Xu J., Zhang Y., Wu J., Li X., Zhao X., Li K., Lu L., Han B. (2019) Role of anlotinib-induced CCL2 decrease in anti-angiogenesis and response prediction for nonsmall cell lung cancer therapy. Eur. Respir. J., 53, 1801562. https://doi.org/10.1183/13993003.01562-2018.
17 Oxnard G. R., Hu Y., Mileham K. F., Husain H., Costa D. B., Tracy P., Feeney N., Sholl L. M., Dahlberg S. E., Redig A. J., Kwiatkowski D. J., Rabin M. S., Paweletz C. P., Thress K. S., Jänne P. A. (2018) Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M–positive lung cancer and acquired resistance to osimertinib. JAMA Oncol., 4, 1527. https://doi.org/10.1001/jamaoncol.2018.2969.
18 Camidge D. R., Dziadziuszko R., Peters S., Mok T., Noe J., Nowicka M., Gadgeel S. M., Cheema P., Pavlakis N., de Marinis F., Cho B. C., Zhang L., Moro-Sibilot D., Liu T., Bordogna W., Balas B., Müller B., Shaw A. T. (2019) Updated efficacy and safety data and impact of the EML4-ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non–small cell lung cancer in the global phase III ALEX study. J. Thorac. Oncol., 14, 1233–1243. https://doi.org/10.1016/j.jtho.2019.03.007.
19 Gupta O., Pradhan T., Chawla G. (2023) An updated review on diverse range of biological activities of 1,2,4-triazole derivatives: Insight into structure–activity relationship. J. Mol. Struct., 1274, 134487. https://doi.org/10.1016/j.molstruc.2022.134487.
20 Czyrski A., Resztak M., Świderski P., Brylak J., Główka F. K. (2021) The overview on the pharmacokinetic and pharmacodynamic interactions of triazoles. Pharmaceutics, 13, 1961. https://doi.org/10.3390/pharmaceutics13111961.
21 Aitouna A. O., Syed A., Alfagham A. T., Mazoir N., de Julián-Ortiz J. V., Elgorban A. M., El Idrissi M., Wong S. L., Zeroual, A. (2024) Investigating the chemical reactivity and molecular docking of 2-diazo-3, 3, 3-trifluoro-1-nitropropane with phenyl methacrylate using computational methods. Chem. Heterocycl. Compd, 60 (11), 592-599. https://doi.org/10.1007/s10593-025-03382-y
22 Klenina O. V., Chaban T. I., Chaban I. H., Lelyukh M. I. (2025) Recent advances in the synthesis of thiazolo [4, 5-b] pyridines. Part 3. Focus on biological activity (microreview). Chem. Heterocycl. Compd., 61 (1/2) 1-4. https://doi.org/10.1007/s10593-025-03398-4
23 Ameur S., Barhoumi A., Abdallaoui H. E. A. E., Syed A., Belghiti M. E., Elgorban A. M., Wong S. L., Wang S., El Idrissi M., Zeroual A., Mazoir, N. (2024) Molecular docking, exploring diverse selectivities and mechanistic insights in the cycloaddition reaction between 3-benzoylpyrrolo-[1, 2-a] quinoxaline-1, 2, 4 (5H)-triones and butyl vinyl ether. Chem. Heterocycl. Compd., 60 (11), 584-591. https://doi.org/10.1007/s10593-025-03381-z
24 Yele V., Pindiprolu S. K. S. S., Sana S., Ramamurty D. S. V. N. M., Madasi J. R. K., Vadlamani, S. (2021) Synthesis and preclinical evaluation of indole triazole conjugates as microtubule targeting agents that are effective against MCF-7 breast cancer cell lines. Anticancer Agents Med. Chem., 21, 1047–1055. https://doi.org/10.2174/1871520620666200925102940.
25 Zahoor A. F., Saeed S., Rasul A., Noreen R., Irfan A., Ahmad S., Faisal S., Al-Hussain S. A., Saeed M. A., Muhammed M. T., Muhammad Z. A., Zaki M. E. A. (2023) Synthesis, cytotoxic, and computational screening of some novel indole–1,2,4-triazole-based S-alkylated N-aryl acetamides. Biomedicines, 11, 3078. https://doi.org/10.3390/biomedicines11113078.
26 Abouelenein M. G., El-Rashedy A. A., Awad H. M., El Farargy A. F., Nassar I. F., Nassrallah, A. (2023) Synthesis, molecular modeling insights, and anticancer assessment of novel polyfunctionalized pyridine congeners. Bioorg. Chem., 141, 106910. https://doi.org/10.1016/j.bioorg.2023.106910.
27 Abouelenein M. G., Mohamed M. B. I., Elsenety M. M., El‐Rashedy A. A., Ghalib S. H., Mohamed F. A. E., El‐Ebiary N. M. A., Ageeli A. A. (2024) Facile and novel synthetic approach, molecular docking, molecular dynamics, and drug‐likeness evaluation of 9‐substituted acridine derivatives as dual anticancer and antimicrobial agents. Chem. Biodivers., 21. https://doi.org/10.1002/cbdv.202301986.
28 Abo-Salem H. M., Gibriel A. A., El Awady M. E., Mandour A. H. (2020) Synthesis, molecular docking and biological evaluation of novel flavone derivatives as potential anticancer agents targeting Akt. Med. Chem. (Los Angeles), 17, 158–170. https://doi.org/10.2174/1573406416666200306115035.
29 Fawzy N. M., Ahmed K. M., Abo-Salem H. M., Aly M. S. (2022) Novel furochromone derivatives of potential anticancer activity targeting EGFR tyrosine kinase: Synthesis and molecular docking study. Russ. J. Bioorg. Chem., 48, 749–767. https://doi.org/10.1134/S1068162022040082.
30 Abo-Salem H. M., El Souda S. S. M., Shafey H. I., Zoheir K. M. A., Ahmed K. M., Mahmoud Kh., Mahrous K. F., Fawzy N. M. (2024) Synthesis, bioactivity assessment, molecular docking and ADMET studies of new chromone congeners exhibiting potent anticancer activity. Sci. Rep., 14, 9636. https://doi.org/10.1038/s41598-024-59606-2.
31 Abdelmegeed H., Abo-Salem H. M., Zayed E. M., El-Sawy E. R. (2024) Anti colorectal cancer activity and in silico studies of novel pyridine nortopsentin analog as cyclin dependent kinase 6 inhibitor. Sci. Rep., 14, 26327. https://doi.org/10.1038/s41598-024-75411-3.
32 Lipinski C. A. (2004) Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today Technol., 1, 337–341. https://doi.org/10.1016/j.ddtec.2004.11.007.
33 Veber D. F., Johnson S. R., Cheng H.-Y., Smith B. R., Ward K. W., Kopple K. D. (2002) Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 45, 2615–2623. https://doi.org/10.1021/jm020017n.
34 Al-blewi F. F., Almehmadi M. A., Aouad M. R., Bardaweel S. K., Sahu P. K., Messali M., Rezki N., El Ashry E. S. H. (2018) Design, synthesis, ADME prediction and pharmacological evaluation of novel benzimidazole-1,2,3-triazole-sulfonamide hybrids as antimicrobial and antiproliferative agents. Chem. Cent. J., 12, 110. https://doi.org/10.1186/s13065-018-0479-1.
35 Flores-Holguín N., Frau J., Glossman-Mitnik D. (2021) In silico pharmacokinetics, ADMET study and conceptual DFT analysis of two plant cyclopeptides isolated from Rosaceae as a computational peptidology approach. Front. Chem., 9. https://doi.org/10.3389/fchem.2021.708364.
36 Pires D.E.V., Blundell T.L., Ascher D.B. (2015) pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem., 58, 4066–4072. https://doi.org/10.1021/acs.jmedchem.5b00104.
37 Sevaille L., Gavara L., Bebrone C., De Luca F., Nauton L., Achard M., Mercuri P., Tanfoni S., Borgianni L., Guyon C., Lonjon P., Turan‐Zitouni G., Dzieciolowski J., Becker K., Bénard L., Condon C., Maillard L., Martinez J., Frère J., Dideberg O., Galleni M., Docquier J., Hernandez J. (2017) 1,2,4‐Triazole‐3‐thione compounds as inhibitors of dizinc metallo‐β‐lactamases. Chem. Med. Chem., 12, 972–985. https://doi.org/10.1002/cmdc.201700186.
38 Souza H., de Sousa R., Lira B., Vilela R., Borges N., de Siqueira Junior J., Lima E., Jardim J., da Silva G., Barbosa Filho J., de Athayde Filho P. (2018) Synthesis, in silico study and antimicrobial evaluation of new selenoglycolicamides. J. Braz. Chem. Soc. https://doi.org/10.21577/0103-5053.20180148
39 Liu K., Zhu C., Liang Y., Min D., Jin Z., Sun X. (2025) Discovery of a novel 1,4-benzodiazepine derivative as a highly selective ANXA3 degrader for the treatment of triple-negative breast cancer. J. Med. Chem., 68, 5358–5381. https://doi.org/10.1021/acs.jmedchem.4c02403.
40 Li Q., Lou Z., Wang C., Li Y. (2025) In vitro anticancer effects in hepatocellular carcinoma (HCC) and protein interaction study of xanthoangelol. Int. J. Biol. Macromol., 302, 138530. https://doi.org/10.1016/j.ijbiomac.2024.138530
41 Trott O., Olson A. J. (2010) AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem, 31 (2), 455–461. https://doi.org/10.1002/jcc.21334
42 Lim J., Kelley E. H., Methot J. L., Zhou H., Petrocchi A., Chen H., Hill S. E., Hinton M. C., Hruza A., Jung J. O., Maclean J. K. F., Mansueto M., Naumov G. N., Philippar U., Raut S., Spacciapoli P., Sun D., Siliphaivanh P. (2016) Discovery of 1-(1H-pyrazolo[4,3-c]pyridin-6-yl)urea inhibitors of extracellular signal-regulated kinase (ERK) for the treatment of cancers. J. Med. Chem., 59 (14), 6501–6511. https://doi.org/10.1021/acs.jmedchem.6b00708.
43 Daina A., Michielin O., Zoete V. (2017) SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 7, 42717. https://doi.org/10.1038/srep42717
44 Pires D. E. V., Blundell T. L., Ascher D. B. (2015) pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem., 58 (9), 4066–4072. https://doi.org/10.1021/acs.jmedchem.5b00104.