Evaluation of Benzamide-Chalcone Derivatives as EGFR/CDK2 Inhibitor: Synthesis,
In-Vitro Inhibition, and Molecular Modeling Studies

Akshada       Joshi; Heena       Bhojwani; Ojas       Wagal; Khushboo       Begwani; Urmila       Joshi; Sadhana       Sathaye; Divya       Kanchan

doi:10.2174/1871520621666210415091359

Abstract

Background: EGFR (Epidermal Growth Factor Receptor) and CDK2 (Cyclin Dependent Kinase 2) are important targets in the treatment of many solid tumors and different ligands of these receptors share many common structural features.

Objective: The study involved the synthesis of benzamide-substituted chalcones and determination of their antiproliferative activity as well as a preliminary evaluation of EGFR and CDK2 inhibitory potential using both receptor binding and computational methods.

Methods: We synthesized 13 benzamide-substituted chalcone derivatives and tested their antiproliferative activity against MCF-7, HT-29 and U373MG cell lines using Sulforhodamine B Assay. Four compounds were examined for activity against EGFR and CDK2 kinase. The compounds were docked into both EGFR and CDK2 using Glide software. The stability of the interactions for the most active compound was evaluated by Molecular Dynamics Simulation using Desmond software. Molecular docking studies on mutant EGFR (T790M, T790M/L858R, and T790M/C797S) were also carried out.

Results: From the SRB assay, we concluded that compounds 1g, and 1k were effective in inhibiting the growth of the MCF-7 cell line whereas the other compounds were moderately active. Most compounds were either moderately active or inactive on U373 MG and HT-29 cell lines. Compounds 1g and 1k showed good inhibitory activity against CDK2 kinase while 1d and 1f were moderately active. Compounds 1d, 1f, 1g, and 1k were moderately active against EGFR kinase. Molecular docking reveals the involvement of one hydrogen bond with Met793 in binding with EGFR; however, it was not stable during the simulation and these compounds bind to the receptor mainly via hydrophobic contacts. This fact also points towards a different orientation of the inhibitor within the active site of EGFR kinase. Binding mode analysis for CDK2 inhibition studies indicates that hydrogen bonding interactions with Lys 33 and Leu83 are important for the activity. These interactions were found to be stable throughout the simulation. Considering the results for wild-type EGFR inhibition, the docking studies on mutants were performed and which indicate that the compounds bind to the mutant EGFR but the amino acid residues involved are similar to the wild-type EGFR, and therefore, the selectivity seems to be limited.

Conclusion: These benzamide-substituted chalcone derivatives will be useful as lead molecules for the further development of newer inhibitors of EGFR and/or CDK2 kinases.

Keywords: Chalcones, SRB assay, EGFR inhibition, CDK2 inhibition, molecular docking, molecular dynamics simulation.

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[1] 
Bayliss, R.; Fry, A.; Haq, T.; Yeoh, S. On the molecular mechanisms of mitotic kinase activation. Open Biol.,  2012, 2(11)120136
[http://dx.doi.org/10.1098/rsob.120136] [PMID:  23226601] 
[2] 
Du, Z.; Lovly, C.M. Mechanisms of receptor tyrosine kinase activation in cancer. Mol. Cancer,  2018, 17(1), 58.
[http://dx.doi.org/10.1186/s12943-018-0782-4] [PMID:  29455648] 
[3] 
Normanno, N.; De Luca, A.; Bianco, C.; Strizzi, L.; Mancino, M.; Maiello, M.R.; Carotenuto, A.; De Feo, G.; Caponigro, F.; Salomon, D.S. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene,  2006, 366(1), 2-16.
[http://dx.doi.org/10.1016/j.gene.2005.10.018] [PMID:  16377102] 
[4] 
Ciardiello, F.; Tortora, G. EGFR antagonists in cancer treatment. N. Engl. J. Med.,  2008, 358(11), 1160-1174.
[http://dx.doi.org/10.1056/NEJMra0707704] [PMID:  18337605] 
[5] 
Shapiro, G.I. Cyclin-dependent kinase pathways as targets for cancer treatment. J. Clin. Oncol.,  2006, 24(11), 1770-1783.
[http://dx.doi.org/10.1200/JCO.2005.03.7689] [PMID:  16603719] 
[6] 
Santo, L.; Siu, K.T.; Raje, N. Targeting cyclin-dependent kinases and cell cycle progression in human cancers. Semin. Oncol.,  2015, 42(6), 788-800.
[http://dx.doi.org/10.1053/j.seminoncol.2015.09.024] [PMID:  26615126] 
[7] 
Tadesse, S.; Caldon, E.C.; Tilley, W.; Wang, S. Cyclin-dependent kinase 2 inhibitors in cancer therapy: An update. J. Med. Chem.,  2019, 62(9), 4233-4251.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01469] [PMID:  30543440] 
[8] 
Yewale, C.; Baradia, D.; Vhora, I.; Patil, S.; Misra, A. Epidermal growth factor receptor targeting in cancer: a review of trends and strategies. Biomaterials,  2013, 34(34), 8690-8707.
[http://dx.doi.org/10.1016/j.biomaterials.2013.07.100] [PMID:  23953842] 
[9] 
Palmieri, L.; Rastelli, G. αC helix displacement as a general approach for allosteric modulation of protein kinases. Drug Discov. Today,  2013, 18(7-8), 407-414.
[http://dx.doi.org/10.1016/j.drudis.2012.11.009] [PMID:  23195331] 
[10] 
Carlino, L.; Christodoulou, M.S.; Restelli, V.; Caporuscio, F.; Foschi, F.; Semrau, M.S.; Costanzi, E.; Tinivella, A.; Pinzi, L.; Lo Presti, L.; Battistutta, R.; Storici, P.; Broggini, M.; Passarella, D.; Rastelli, G. Structure-activity relationships of hexahydrocyclopenta[c]quinoline derivatives as allosteric inhibitors of CDK2 and EGFR. ChemMedChem,  2018, 13(24), 2627-2634.
[http://dx.doi.org/10.1002/cmdc.201800687] [PMID:  30457710] 
[11] 
Stamos, J.; Sliwkowski, M.X.; Eigenbrot, C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J. Biol. Chem.,  2002, 277(48), 46265-46272.
[http://dx.doi.org/10.1074/jbc.M207135200] [PMID:  12196540] 
[12] 
Shewchuk, L.; Hassell, A.; Wisely, B.; Rocque, W.; Holmes, W.; Veal, J.; Kuyper, L.F. Binding mode of the 4-anilinoquinazoline class of protein kinase inhibitor: X-ray crystallographic studies of 4-anilinoquinazolines bound to cyclin-dependent kinase 2 and p38 kinase. J. Med. Chem.,  2000, 43(1), 133-138.
[http://dx.doi.org/10.1021/jm990401t] [PMID:  10633045] 
[13] 
Romu, A.A.; Lei, Z.; Zhou, B.; Chen, Z.S.; Korlipara, V. Design, synthesis and biological evaluation of WZ4002 analogues as EGFR inhibitors. Bioorg. Med. Chem. Lett.,  2017, 27(21), 4832-4837.
[http://dx.doi.org/10.1016/j.bmcl.2017.09.048] [PMID:  28974338] 
[14] 
Wang, S.; Griffiths, G.; Midgley, C.A.; Barnett, A.L.; Cooper, M.; Grabarek, J.; Ingram, L.; Jackson, W.; Kontopidis, G.; McClue, S.J.; McInnes, C.; McLachlan, J.; Meades, C.; Mezna, M.; Stuart, I.; Thomas, M.P.; Zheleva, D.I.; Lane, D.P.; Jackson, R.C.; Glover, D.M.; Blake, D.G.; Fischer, P.M. Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents. Chem. Biol.,  2010, 17(10), 1111-1121.
[http://dx.doi.org/10.1016/j.chembiol.2010.07.016] [PMID:  21035734] 
[15] 
Luk, K.C.; Simcox, M.E.; Schutt, A.; Rowan, K.; Thompson, T.; Chen, Y.; Kammlott, U.; DePinto, W.; Dunten, P.; Dermatakis, A. A new series of potent oxindole inhibitors of CDK2. Bioorg. Med. Chem. Lett.,  2004, 14(4), 913-917.
[http://dx.doi.org/10.1016/j.bmcl.2003.12.009] [PMID:  15012993] 
[16] 
Maadwar, S.; Galla, R. Cytotoxic oxindole derivatives: In vitro EGFR
 inhibition, pharmacophore modeling, 3D-QSAR and molecular dynamics
  studies. J. Recept. Signal Transduct.,,  2019, 1-10.
[http://dx.doi.org/10.1080/10799893.2019.1683865] 
[17] 
Gavriil, E.S.; Doukatas, A.; Karampelas, T.; Myrianthopoulos, V.; Dimitrakis, S.; Mikros, E.; Marakos, P.; Tamvakopoulos, C.; Pouli, N. Design, synthesis and biological evaluation of novel substituted purine isosters as EGFR kinase inhibitors, with promising pharmacokinetic profile and in vivo efficacy. Eur. J. Med. Chem.,  2019, 176, 393-409.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.029] [PMID:  31125894] 
[18] 
De Azevedo, W.F.; Leclerc, S.; Meijer, L.; Havlicek, L.; Strnad, M.; Kim, S.H. Inhibition of cyclin-dependent kinases by purine analogues: Crystal structure of human cdk2 complexed with roscovitine. Eur. J. Biochem.,  1997, 243(1-2), 518-526.
[http://dx.doi.org/10.1111/j.1432-1033.1997.0518a.x] [PMID:  9030780] 
[19] 
Ren, W.; Qiao, Z.; Wang, H.; Zhu, L.; Zhang, L. Flavonoids: Promising anticancer agents. Med. Res. Rev.,  2003, 23(4), 519-534.
[http://dx.doi.org/10.1002/med.10033] [PMID:  12710022] 
[20] 
Kasi, P.D.; Tamilselvam, R.; Skalicka-Woźniak, K.; Nabavi, S.F.; Daglia, M.; Bishayee, A.; Pazoki-Toroudi, H.; Nabavi, S.M. Molecular targets of curcumin for cancer therapy: An updated review. Tumour Biol.,  2016, 37(10), 13017-13028.
[http://dx.doi.org/10.1007/s13277-016-5183-y] [PMID:  27468716] 
[21] 
Rodrigues, F.C.; Anil Kumar, N.V.; Thakur, G. Developments in the anticancer activity of structurally modified curcumin: An up-to-date review. Eur. J. Med. Chem.,  2019, 177, 76-104.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.058] [PMID:  31129455] 
[22] 
Xu, Y.Y.; Cao, Y.; Ma, H.; Li, H.Q.; Ao, G.Z. Design, synthesis and molecular docking of α,β-unsaturated cyclohexanone analogous of curcumin as potent EGFR inhibitors with antiproliferative activity. Bioorg. Med. Chem.,  2013, 21(2), 388-394.
[http://dx.doi.org/10.1016/j.bmc.2012.11.031] [PMID:  23245570] 
[23] 
Reddy, N.S.; Gumireddy, K.; Mallireddigari, M.R.; Cosenza, S.C.; Venkatapuram, P.; Bell, S.C.; Reddy, E.P.; Reddy, M.V.R. Novel coumarin-3-(N-aryl)carboxamides arrest breast cancer cell growth by inhibiting ErbB-2 and ERK1. Bioorg. Med. Chem.,  2005, 13(9), 3141-3147.
[http://dx.doi.org/10.1016/j.bmc.2005.02.051] [PMID:  15809149] 
[24] 
Thakur, A.; Singla, R.; Jaitak, V. Coumarins as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies. Eur. J. Med. Chem.,  2015, 101, 476-495.
[http://dx.doi.org/10.1016/j.ejmech.2015.07.010] [PMID:  26188907] 
[25] 
Zhu, Z.W.; Shi, L.; Ruan, X.M.; Yang, Y.; Li, H.Q.; Xu, S.P.; Zhu, H.L. Synthesis and antiproliferative activities against Hep-G2 of salicylanide derivatives: Potent inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase. J. Enzyme Inhib. Med. Chem.,  2011, 26(1), 37-45.
[http://dx.doi.org/10.3109/14756361003671060] [PMID:  20583855] 
[26] 
Deng, W.; Guo, Z.; Guo, Y.; Feng, Z.; Jiang, Y.; Chu, F. Acryloylamino-salicylanilides as EGFR PTK inhibitors. Bioorg. Med. Chem. Lett.,  2006, 16(2), 469-472.
[http://dx.doi.org/10.1016/j.bmcl.2005.06.088] [PMID:  16275081] 
[27] 
Tantawy, M.A.; Sroor, F.M.; Mohamed, M.F.; El-Naggar, M.E.; Saleh, F.M.; Hassaneen, H.M.; Abdelhamid, I.A. Molecular docking study, cytotoxicity, cell cycle arrest and apoptotic induction of novel chalcones incorporating thiadiazolyl isoquinoline in cervical cancer. Anticancer. Agents Med. Chem.,  2020, 20(1), 70-83.
[http://dx.doi.org/10.2174/1871520619666191024121116] [PMID:  31696811] 
[28] 
Chu, S.S.; Alegria, L.A.; Bleckman, T.M.; Chong, W.K.M.; Duvadie, R.K.; Li, L.; Reich, S.H.; Romines, W.H., III; Wallace, M.B.; Yang, Y. Thiazole
 benzamide derivatives and pharmaceutical compositions for inhibiting cell
 proliferation. U.S. Patent 6,720,346, April;132004, 
[29] 
Bradshaw, J.; Clitherow, J.W. Benzanilide derivatives. U.S. Patent
 5,358,948A, October;251994, 
[30] 
Biagi, G.; Giorgi, I.; Livi, O.; Nardi, A.; Calderone, V.; Martelli, A.; Martinotti, E.; LeRoy Salerni, O. Synthesis and biological activity of novel substituted benzanilides as potassium channel activators. V. Eur. J. Med. Chem.,  2004, 39(6), 491-498.
[http://dx.doi.org/10.1016/j.ejmech.2004.02.006] [PMID:  15183907] 
[31] 
Bhagat, S.; Sharma, R.; Sawant, D.M.; Sharma, L.; Chakraborti, A.K. LiOH•H2O as a novel dual activation catalyst for highly efficient and easy synthesis of 1,3-diaryl-2-propenones by claisen-schmidt condensation under mild conditions. J. Mol. Catal. Chem.,  2006, 244(1-2), 20-24.
[http://dx.doi.org/10.1016/j.molcata.2005.08.039] 
[32] 
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst.,  1990, 82(13), 1107-1112.
[http://dx.doi.org/10.1093/jnci/82.13.1107] [PMID:  2359136] 
[33] 
Vichai, V.; Kirtikara, K.; Sulforhodamine, B. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat. Protoc.,  2006, 1(3), 1112-1116.
[http://dx.doi.org/10.1038/nprot.2006.179] [PMID:  17406391] 
[34] 
Zegzouti, H.; Zdanovskaia, M.; Hsiao, K.; Goueli, S.A. ADP-Glo: A Bioluminescent and homogeneous ADP monitoring assay for kinases. Assay Drug Dev. Technol.,  2009, 7(6), 560-572.
[http://dx.doi.org/10.1089/adt.2009.0222] [PMID:  20105026] 
[35] 
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem.,  2004, 47(7), 1739-1749.
[http://dx.doi.org/10.1021/jm0306430] [PMID:  15027865] 
[36] 
Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem.,  2004, 47(7), 1750-1759.
[http://dx.doi.org/10.1021/jm030644s] [PMID:  15027866] 
[37] 
Kumar, B.S.; Prasad, A.R.G.; Reddy, P.R.; Ravindranath, L.K. Synthesis, antimicrobial and in silico egfr inhibitory activity evaluation of sulfonylamino pyrrolidine derivatives. Pharm. Chem. J.,  2016, 50(7), 443-450.
[http://dx.doi.org/10.1007/s11094-016-1467-1] 
[38] 
Aly, R.M.; Serya, R.A.T.; El-Motwally, A.M.; Esmat, A.; Abbas, S.; Abou El Ella, D.A. Novel quinoline-3-carboxamides (Part 2): Design, optimization and synthesis of quinoline based scaffold as EGFR inhibitors with potent anticancer activity. Bioorg. Chem.,  2017, 75, 368-392.
[http://dx.doi.org/10.1016/j.bioorg.2017.10.018] [PMID:  29096097] 
[39] 
Joshi, A.; Bhojwani, H.; Joshi, U. Selection of best crystal structure for initiating docking-based virtual screening studies of CDK2 inhibitors: A cross-docking and dud set validation approach. Indian Drugs,  2019, 56(6), 77-85.
[40] 
Release, S. 2017-1: LigPrep; Schrödinger, LLC: New York, NY, 2017. 
[41] 
Jorgensen, W.L.; Tirado-Rives, J. The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin. J. Am. Chem. Soc.,  1988, 110(6), 1657-1666.
[http://dx.doi.org/10.1021/ja00214a001] [PMID:  27557051] 
[42] 
Jorgensen, W.L.; Maxwell, D.S.; Tirado-Rives, J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J. Am. Chem. Soc.,  1996, 118(45), 11225-11236.
[http://dx.doi.org/10.1021/ja9621760] 
[43] 
Release, S. 2017-1: protein preparation wizard; Epik, Schrödinger, LLC, New York, NY, 2017; Impact, Schrödinger, LLC: New York, NY, 2017. 
[44] 
Release, S. 2017-1: Glide; Schrödinger, LLC: New York, NY, 2017. 
[45] 
Release, S. 2016-4: Desmond molecular dynamics system; D. E. Shaw Research: New York, NY, 2016. 
[46] 
Bowers, K.J.; Chow, E.; Xu, H.; Dror, R.O.; Eastwood, M.P.; Gregersen, B.A.; Klepeis, J.L.; Kolossvary, I.; Moraes, M.A.; Sacerdoti, F.D.; Salmon, J.K.; Shan, Y.; Shaw, D.E. Scalable algorithms for molecular dynamics simulations on commodity clusters. Proceedings of the 2006 ACM/IEEE Conference on Supercomputing, SC’06, 2006.
[http://dx.doi.org/10.1109/SC.2006.54] 
[47] 
Jorgensen, W.L.; Chandrasekhar, J.; Madura, J.D.; Impey, R.W.; Klein, M.L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys.,  1983, 79(2), 926-935.
[http://dx.doi.org/10.1063/1.445869] 
[48] 
Ryckaert, J.P.; Ciccotti, G.; Berendsen, H.J.C. Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-Alkanes. J. Comput. Phys.,  1977, 23(3), 327-341.
[http://dx.doi.org/10.1016/0021-9991(77)90098-5] 
[49] 
Lambrakos, S.G.; Boris, J.P.; Oran, E.S.; Chandrasekhar, I.; Nagumo, M. A Modified shake algorithm for maintaining rigid bonds in molecular dynamics simulations of large molecules. J. Comput. Phys.,  1989, 85(2), 473-486.
[http://dx.doi.org/10.1016/0021-9991(89)90160-5] 
[50] 
Tuckerman, M.; Berne, B.J.; Martyna, G.J. Reversible multiple time scale molecular dynamics. J. Chem. Phys.,  1992, 97, 1990-2001.
[http://dx.doi.org/10.1063/1.463137] 
[51] 
Martyna, G.J.; Tobias, D.J.; Klein, M.L. Constant pressure molecular dynamics algorithms. J. Chem. Phys.,  1994, 101, 4177-4189.
[http://dx.doi.org/10.1063/1.467468] 
[52] 
Talele, T.T.; McLaughlin, M.L. Molecular docking/dynamics studies of Aurora A kinase inhibitors. J. Mol. Graph. Model.,  2008, 26(8), 1213-1222.
[http://dx.doi.org/10.1016/j.jmgm.2007.11.003] [PMID:  18096419] 
[53] 
Qureshi, S.I.; Chaudhari, H.K. Design, synthesis, in silico studies and biological screening of quinazolinone analogues as potential antibacterial agents against MRSA. Bioorg. Med. Chem.,  2019, 27(12), 2676-2688.
[http://dx.doi.org/10.1016/j.bmc.2019.05.012] [PMID:  31103406] 
[54] 
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep.,  2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID:  28256516] 
[55] 
Silverstein, R.M.; Bassler, G.C. Spectrometric identification of organic compounds  6th ed.; Jhon Wiley and Sons (Print Edition),; , 2006. 
[56] 
von Achenbach, C.; Weller, M.; Szabo, E. Epidermal growth factor receptor and ligand family expression and activity in glioblastoma. J. Neurochem.,  2018, 147(1), 99-109.
[http://dx.doi.org/10.1111/jnc.14538] [PMID:  29953622] 
[57] 
Manupati, K.; Dhoke, N.R.; Debnath, T.; Yeeravalli, R.; Guguloth, K.; Saeidpour, S.; De, U.C.; Debnath, S.; Das, A. Inhibiting epidermal growth factor receptor signalling potentiates mesenchymal-epithelial transition of breast cancer stem cells and their responsiveness to anticancer drugs. FEBS J.,  2017, 284(12), 1830-1854.
[http://dx.doi.org/10.1111/febs.14084] [PMID:  28398698] 
[58] 
Luca, A.C.; Mersch, S.; Deenen, R.; Schmidt, S.; Messner, I.; Schäfer, K.L.; Baldus, S.E.; Huckenbeck, W.; Piekorz, R.P.; Knoefel, W.T.; Krieg, A.; Stoecklein, N.H. Impact of the 3D microenvironment on phenotype, gene expression, and EGFR inhibition of colorectal cancer cell lines. PLoS One,  2013, 8(3)e59689
[http://dx.doi.org/10.1371/journal.pone.0059689] [PMID:  23555746] 
[59] 
Tadesse, S.; Anshabo, A.T.; Portman, N.; Lim, E.; Tilley, W.; Caldon, C.E.; Wang, S. Targeting CDK2 in cancer: Challenges and opportunities for therapy. Drug Discov. Today,  2020, 25(2), 406-413.
[http://dx.doi.org/10.1016/j.drudis.2019.12.001] [PMID:  31839441] 
[60] 
Abou-Zied, H.A.; Youssif, B.G.M.; Mohamed, M.F.A.; Hayallah, A.M.; Abdel-Aziz, M. EGFR inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and docking studies of novel xanthine derivatives carrying chalcone moiety as hybrid molecules. Bioorg. Chem.,  2019, 89102997
[http://dx.doi.org/10.1016/j.bioorg.2019.102997] [PMID:  31136902] 
[61] 
Pawar, C.D.; Chavan, S.L.; Pawar, U.D.; Pansare, D.N.; Deshmukh, S.V.; Shinde, D.B. Synthesis, Anti-Proliferative Activity, SAR, and Kinase Inhibition Studies of Thiazol-2-Yl- Substituted Sulfonamide Derivatives. J. Chin. Chem. Soc. (Taipei),  2019, 66(3), 257-264.
[http://dx.doi.org/10.1002/jccs.201800312] 
[62] 
Tu, Y.; Wang, C.; Xu, S.; Lan, Z.; Li, W.; Han, J.; Zhou, Y.; Zheng, P.; Zhu, W. Design, synthesis, and docking studies of quinazoline analogues bearing aryl semicarbazone scaffolds as potent EGFR inhibitors. Bioorg. Med. Chem.,  2017, 25(12), 3148-3157.
[http://dx.doi.org/10.1016/j.bmc.2017.04.001] [PMID:  28428040] 
[63] 
Ghorab, M.M.; Abdel-Kader, M.S.; Alqahtani, A.S.; Soliman, A.M. Synthesis of some quinazolinones inspired from the natural alkaloid L-norephedrine as EGFR inhibitors and radiosensitizers. J. Enzyme Inhib. Med. Chem.,  2021, 36(1), 218-237.
[http://dx.doi.org/10.1080/14756366.2020.1854243] [PMID:  33357002] 
[64] 
Eldehna, W.M.; Al-Rashood, S.T.; Al-Warhi, T.; Eskandrani, R.O.; Alharbi, A.; El Kerdawy, A.M. Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3β inhibitors targeting breast cancer: Design, synthesis, biological evaluation, and in silico studies. J. Enzyme Inhib. Med. Chem.,  2021, 36(1), 270-285.
[http://dx.doi.org/10.1080/14756366.2020.1862101] [PMID:  33327806] 
[65] 
Shawky, A.M.; Ibrahim, N.A.; Abourehab, M.A.S.; Abdalla, A.N.; Gouda, A.M. Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities. J. Enzyme Inhib. Med. Chem.,  2021, 36(1), 15-33.
[http://dx.doi.org/10.1080/14756366.2020.1837124] [PMID:  33103497] 
[66] 
Wu, J.; Chen, W.; Xia, G.; Zhang, J.; Shao, J.; Tan, B.; Zhang, C.; Yu, W.; Weng, Q.; Liu, H.; Hu, M.; Deng, H.; Hao, Y.; Shen, J.; Yu, Y. Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting EGFR. ACS Med. Chem. Lett.,  2013, 4(10), 974-978.
[http://dx.doi.org/10.1021/ml4002437] [PMID:  24900594] 
[67] 
Patel, H.M.; Pawara, R.; Ansari, A.; Noolvi, M.; Surana, S. Design and synthesis of quinazolinones as EGFR inhibitors to overcome EGFR resistance obstacle. Bioorg. Med. Chem.,  2017, 25(10), 2713-2723.
[http://dx.doi.org/10.1016/j.bmc.2017.03.039] [PMID:  28366268] 
[68] 
Fathalla, O.A.E.F.M.; Ismail, M.A.H.; Anwar, M.M.; Abouzid, K.A.M.; Ramadan, A.A.K. Novel 2-Thiopyrimidine derivatives as CDK2 inhibitors: Molecular modeling, synthesis, and anti-tumor activity evaluation. Med. Chem. Res.,  2013, 22(2), 659-673.
[http://dx.doi.org/10.1007/s00044-012-0051-9] 
[69] 
Ghorab, M.M.; Ragab, F.A.; Heiba, H.I.; Elsayed, M.S.A.; Ghorab, W.M. Design, synthesis and molecular modeling study of certain 4-Methylbenzenesulfonamides with CDK2 inhibitory activity as anticancer and radio-sensitizing agents. Bioorg. Chem.,  2018, 80, 276-287.
[http://dx.doi.org/10.1016/j.bioorg.2018.06.010] [PMID:  29966874] 
[70] 
Choowongkomon, K.; Sawatdichaikul, O.; Songtawee, N.; Limtrakul, J. Receptor-based virtual screening of EGFR kinase inhibitors from the NCI diversity database. Molecules,  2010, 15(6), 4041-4054.
[http://dx.doi.org/10.3390/molecules15064041] [PMID:  20657425] 
[71] 
Xing, L.; Klug-Mcleod, J.; Rai, B.; Lunney, E.A. Kinase hinge binding scaffolds and their hydrogen bond patterns. Bioorg. Med. Chem.,  2015, 23(19), 6520-6527.
[http://dx.doi.org/10.1016/j.bmc.2015.08.006] [PMID:  26358279] 
[72] 
Lim, S.M.; Jeong, Y.; Hong, S. Strategies to overcome acquired resistances conferred by mutations in the kinase domain of EGFR. Future Med. Chem.,  2016, 8(8), 853-878.
[http://dx.doi.org/10.4155/fmc-2016-0019] [PMID:  27195594] 
[73] 
He, J.; Zhou, Z.; Sun, X.; Yang, Z.; Zheng, P.; Xu, S.; Zhu, W. The new opportunities in medicinal chemistry of fourth-generation EGFR inhibitors to overcome C797S mutation. Eur. J. Med. Chem.,  2021, 210112995Available from: ,  https://doi.org/https://doi.org/10.1016/j.ejmech.2020.112995
[http://dx.doi.org/10.1016/j.ejmech.2020.112995] [PMID:  33243531] 
[74] 
Park, H.; Jung, H.Y.; Kim, K.; Kim, M.; Hong, S. Rational computational design of fourth-generation egfr inhibitors to combat drug-resistant non-small cell lung cancer. Int. J. Mol. Sci.,  2020, 21(23), 9323.
[http://dx.doi.org/10.3390/ijms21239323] [PMID:  33297461] 

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DOI https://dx.doi.org/10.2174/1871520621666210415091359	Print ISSN 1871-5206
Publisher Name Bentham Science Publisher	Online ISSN 1875-5992

Anti-Cancer Agents in Medicinal Chemistry

Evaluation of Benzamide-Chalcone Derivatives as EGFR/CDK2 Inhibitor: Synthesis, In-Vitro Inhibition, and Molecular Modeling Studies

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