Privileged Scaffolds in Drug Discovery against Human Epidermal Growth Factor
Receptor 2 for Cancer Treatment

Mudasir Nabi      Peerzada; Rania      Hamdy; Masood Ahmad      Rizvi; Saurabh      Verma
doi:10.2174/0113816128283615231218094706
Abstract

HER2 is the membrane receptor tyrosine kinase showing overexpression in several human malignancies, particularly breast cancer. HER2 overexpression causes the activation of Ras- MAPK and PI3K/Akt/ NF-κB cellular signal transduction pathways that lead to cancer development and progression. HER2 is, therefore, presumed as one of the key targets for the development of tumor-specific therapies. Several preclinical have been developed that function by inhibiting the HER2 tyrosine kinase activity through the prevention of the dimerization process. Most HER2 inhibitors act as ATP competitors and prevent the process of phosphorylation, and abort the cell cycle progression and proliferation. In this review, the clinical drug candidates and potent pre-clinical newly developed molecules are described, and the core chemical scaffolds typically responsible for anti-HER2 activity are deciphered. In addition, the monoclonal antibodies that are either used in monotherapy or in combination therapy against HER2-positive cancer are briefly described. The identified key moieties in this study could result in the discovery of more effective HER2-targeted anticancer drug molecules and circumvent the development of resistance by HER2-specific chemotherapeutics in the future.
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[1]
Hynes NE, Lane HA. ERBB receptors and cancer: The complexity of targeted inhibitors. Nat Rev Cancer  2005; 5(5): 341-54.
 [http://dx.doi.org/10.1038/nrc1609] [PMID: 15864276]

[2]
Brennan PJ, Kumogai T, Berezov A, Murali R, Greene MI. HER2/Neu: Mechanisms of dimerization/oligomerization. Oncogene  2000; 19(53): 6093-101.
 [http://dx.doi.org/10.1038/sj.onc.1203967] [PMID: 11156522]

[3]
Wee P, Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers  2017; 9(5): 52.
 [http://dx.doi.org/10.3390/cancers9050052] [PMID: 28513565]

[4]
Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov  2009; 8(8): 627-44.
 [http://dx.doi.org/10.1038/nrd2926] [PMID: 19644473]

[5]
English DP, Roque DM, Santin AD. HER2 expression beyond breast cancer: Therapeutic implications for gynecologic malignancies. Mol Diagn Ther  2013; 17(2): 85-99.
 [http://dx.doi.org/10.1007/s40291-013-0024-9] [PMID: 23529353]

[6]
Engel RH, Kaklamani VG. HER2-positive breast cancer: Current and future treatment strategies. Drugs  2007; 67(9): 1329-41.
 [http://dx.doi.org/10.2165/00003495-200767090-00006] [PMID: 17547474]

[7]
Schlam I, Swain SM. HER2-positive breast cancer and tyrosine kinase inhibitors: The time is now. NPJ Breast Cancer  2021; 7(1): 56.
 [http://dx.doi.org/10.1038/s41523-021-00265-1] [PMID: 34016991]

[8]
Bender LM, Nahta R. HER2 cross talk and therapeutic resistance in breast cancer. Front Biosci  2008; (13): 3906-12.
 [http://dx.doi.org/10.2741/2978] [PMID: 18508484]

[9]
Oh DY, Bang YJ. HER2-targeted therapies - A role beyond breast cancer. Nat Rev Clin Oncol  2020; 17(1): 33-48.
 [http://dx.doi.org/10.1038/s41571-019-0268-3] [PMID: 31548601]

[10]
Peerzada MN, Khan P, Khan NS, et al. Identification of morpholine based hydroxylamine analogues: Selective inhibitors of MARK4/Par-1d causing cancer cell death through apoptosis. New J Chem  2020; 44(38): 16626-37.
 [http://dx.doi.org/10.1039/D0NJ03474F]

[11]
Peerzada MN, Khan P, Khan NS, et al. Design and development of small-molecule Arylaldoxime/5-nitroimidazole hybrids as potent inhibitors of MARK4: A promising approach for target-based cancer therapy. ACS Omega  2020; 5(36): 22759-71.
 [http://dx.doi.org/10.1021/acsomega.0c01703]

[12]
Peerzada MN, Khan P, Ahmad K, Hassan MI, Azam A. Synthesis, characterization and biological evaluation of tertiary sulfonamide derivatives of pyridyl-indole based heteroaryl chalcone as potential carbonic anhydrase IX inhibitors and anticancer agents. Eur J Med Chem  2018; 155: 13-23.
 [http://dx.doi.org/10.1016/j.ejmech.2018.05.034] [PMID: 29852328]

[13]
Peerzada MN, Hamel E, Bai R, Supuran CT, Azam A. Deciphering the key heterocyclic scaffolds in targeting microtubules, kinases and carbonic anhydrases for cancer drug development. Pharmacol Ther  2021; 225: 107860.
 [http://dx.doi.org/10.1016/j.pharmthera.2021.107860] [PMID: 33895188]

[14]
Masoud V, Pagès G. Targeted therapies in breast cancer: New challenges to fight against resistance. World J Clin Oncol  2017; 8(2): 120-34.
 [http://dx.doi.org/10.5306/wjco.v8.i2.120] [PMID: 28439493]

[15]
Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: An evolving paradigm. Nat Rev Cancer  2013; 13(10): 714-26.
 [http://dx.doi.org/10.1038/nrc3599] [PMID: 24060863]

[16]
Kabraji S, Ni J, Lin NU, Xie S, Winer EP, Zhao JJ. Drug resistance in HER2-positive breast cancer brain metastases: Blame the barrier or the brain? Clin Cancer Res  2018; 24(8): 1795-804.
 [http://dx.doi.org/10.1158/1078-0432.CCR-17-3351] [PMID: 29437794]

[17]
Peerzada MN, Vullo D, Paoletti N, et al. Discovery of novel hydroxyimine-tethered benzenesulfonamides as potential human carbonic anhydrase IX/XII inhibitors. ACS Med Chem Lett  2023; 14(6): 810-9.
 [http://dx.doi.org/10.1021/acsmedchemlett.3c00094] [PMID: 37312840]

[18]
Nami B, Maadi H, Wang Z. Mechanisms underlying the action and synergism of trastuzumab and pertuzumab in targeting HER2-positive breast cancer. Cancers  2018; 10(10): 342.
 [http://dx.doi.org/10.3390/cancers10100342] [PMID: 30241301]

[19]
Canonici A, Ivers L, Conlon NT, et al. HER-targeted tyrosine kinase inhibitors enhance response to trastuzumab and pertuzumab in HER2-positive breast cancer. Invest New Drugs  2019; 37(3): 441-51.
 [http://dx.doi.org/10.1007/s10637-018-0649-y] [PMID: 30062574]

[20]
Yu S, Liu Q, Han X, et al. Development and clinical application of anti-HER2 monoclonal and bispecific antibodies for cancer treatment. Exp Hematol Oncol  2017; 6(1): 31.
 [http://dx.doi.org/10.1186/s40164-017-0091-4] [PMID: 29209558]

[21]
Blumenthal GM, Scher NS, Cortazar P, et al. First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer. Clin Cancer Res  2013; 19(18): 4911-6.
 [http://dx.doi.org/10.1158/1078-0432.CCR-13-1212] [PMID: 23801166]

[22]
Albanell J, Codony J, Rovira A, Mellado B, Gascón P. Mechanism of action of anti-HER2 monoclonal antibodies: Scientific update on trastuzumab and 2C4. Adv Exp Med Biol  2003; 532: 253-68.
 [http://dx.doi.org/10.1007/978-1-4615-0081-0_21]

[23]
Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol  2002; 20(3): 719-26.
 [http://dx.doi.org/10.1200/JCO.2002.20.3.719] [PMID: 11821453]

[24]
Zhang Y, Wu S, Zhuang X, et al. Identification of an activating mutation in the extracellular domain of HER2 conferring resistance to pertuzumab. OncoTargets Ther  2019; 12: 11597-608.
 [http://dx.doi.org/10.2147/OTT.S232912] [PMID: 31920346]

[25]
Luque-Cabal M, García-Teijido P, Fernández-Pérez Y, Sánchez-Lorenzo L, Palacio-Vázquez I. Mechanisms behind the resistance to trastuzumab in HER2-amplified breast cancer and strategies to overcome it. Clin Med Insights Oncol  2016; 10s1(Suppl. 1): CMO.S34537.
 [http://dx.doi.org/10.4137/CMO.S34537] [PMID: 27042153]

[26]
von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med  2017; 377(2): 122-31.
 [http://dx.doi.org/10.1056/NEJMoa1703643] [PMID: 28581356]

[27]
Jagosky M, Tan AR. Combination of pertuzumab and trastuzumab in the treatment of HER2-positive early breast cancer: A review of the emerging clinical data. Breast Cancer  2021; 13: 393-407.
 [http://dx.doi.org/10.2147/BCTT.S176514] [PMID: 34163239]

[28]
Xu Z, Guo D, Jiang Z, et al. Novel HER2-targeting antibody-drug conjugates of trastuzumab beyond T-DM1 in breast cancer: Trastuzumab Deruxtecan (DS-8201a) and (Vic-)trastuzumab duocarmazine (SYD985). Eur J Med Chem  2019; 183: 111682.
 [http://dx.doi.org/10.1016/j.ejmech.2019.111682] [PMID: 31563805]

[29]
Cruz E, Kayser V. Monoclonal antibody therapy of solid tumors: Clinical limitations and novel strategies to enhance treatment efficacy. Biologics  2019; 13: 33-51.
 [http://dx.doi.org/10.2147/BTT.S166310] [PMID: 31118560]

[30]
Baxevanis CN, Perez SA, Papamichail M. Combinatorial treatments including vaccines, chemotherapy and monoclonal antibodies for cancer therapy. Cancer Immunol Immunother  2009; 58(3): 317-24.
 [http://dx.doi.org/10.1007/s00262-008-0576-4] [PMID: 18704409]

[31]
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med  2001; 344(11): 783-92.
 [http://dx.doi.org/10.1056/NEJM200103153441101] [PMID: 11248153]

[32]
Rimawi M, Ferrero JM, de la Haba-Rodriguez J, et al. First-line trastuzumab plus an aromatase inhibitor, with or without pertuzumab, in human epidermal growth factor receptor 2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (PERTAIN): A randomized, open-label phase II trial. J Clin Oncol  2018; 36(28): 2826-35.
 [http://dx.doi.org/10.1200/JCO.2017.76.7863] [PMID: 30106636]

[33]
Scaltriti M, Verma C, Guzman M, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene  2009; 28(6): 803-14.
 [http://dx.doi.org/10.1038/onc.2008.432] [PMID: 19060928]

[34]
Yu AF, Manrique C, Pun S, et al. Cardiac safety of paclitaxel plus trastuzumab and pertuzumab in patients with HER2-positive metastatic breast cancer. Oncologist  2016; 21(4): 418-24.
 [http://dx.doi.org/10.1634/theoncologist.2015-0321] [PMID: 26984450]

[35]
Upton R, Banuelos A, Feng D, et al. Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance. Proc Natl Acad Sci USA  2021; 118(29): e2026849118.
 [http://dx.doi.org/10.1073/pnas.2026849118] [PMID: 34257155]

[36]
Januškevičienė I, Petrikaitė V. Heterogeneity of breast cancer: The importance of interaction between different tumor cell populations. Life Sci  2019; 239: 117009.
 [http://dx.doi.org/10.1016/j.lfs.2019.117009] [PMID: 31669239]

[37]
Pernas S, Tolaney SM. HER2-positive breast cancer: New therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol  2019; 11: 1758835919833519.
 [http://dx.doi.org/10.1177/1758835919833519] [PMID: 30911337]

[38]
Kiewe P, Thiel E. Ertumaxomab: A trifunctional antibody for breast cancer treatment. Expert Opin Investig Drugs  2008; 17(10): 1553-8.
 [http://dx.doi.org/10.1517/13543784.17.10.1553] [PMID: 18808314]

[39]
Kiewe P, Hasmüller S, Kahlert S, et al. Phase I trial of the trifunctional anti-HER2 x anti-CD3 antibody ertumaxomab in metastatic breast cancer. Clin Cancer Res  2006; 12(10): 3085-91.
 [http://dx.doi.org/10.1158/1078-0432.CCR-05-2436] [PMID: 16707606]

[40]
Dillon PM, Tushir-Singh J, Lum LG. Bispecific antibodies for the treatment of breast cancer. Expert Opin Biol Ther  2022; 22(8): 1017-27.
 [http://dx.doi.org/10.1080/14712598.2021.1922665] [PMID: 33896311]

[41]
Weiner LM, Murray JC, Shuptrine CW. Antibody-based immunotherapy of cancer. Cell  2012; 148(6): 1081-4.
 [http://dx.doi.org/10.1016/j.cell.2012.02.034] [PMID: 22424219]

[42]
Higgins MJ, Gabrail NY, Miller K, et al. A phase I/II study of MM-111, a novel bispecific antibody that targets the ErB2/ErB3 heterodimer, in combination with trastuzumab in advanced refractory HER2-positive breast cancer. J Clin Oncol  2011; 29(15) (Suppl.): TPS119-9.
 [http://dx.doi.org/10.1200/jco.2011.29.15_suppl.tps119]

[43]
Marti JLG, Hyder T, Nasrazadani A, Brufsky AM. The evolving landscape of HER2-directed breast cancer therapy. Curr Treat Options Oncol  2020; 21(10): 82.
 [http://dx.doi.org/10.1007/s11864-020-00780-6] [PMID: 32767149]

[44]
Baah S, Laws M, Rahman KM. Antibody-drug conjugates-A tutorial review. Molecules  2021; 26(10): 2943.
 [http://dx.doi.org/10.3390/molecules26102943] [PMID: 34063364]

[45]
Theocharopoulos C, Lialios PP, Samarkos M, Gogas H, Ziogas DC. Antibody-drug conjugates: Functional principles and applications in oncology and beyond. Vaccines  2021; 9(10): 1111.
 [http://dx.doi.org/10.3390/vaccines9101111] [PMID: 34696218]

[46]
Meleti VR, Esperandim VR, Flauzino LGB, et al. (±)-Licarin A and its semi-synthetic derivatives: In vitro and in silico evaluation of trypanocidal and schistosomicidal activities. Acta Trop  2020; 202: 105248.
 [http://dx.doi.org/10.1016/j.actatropica.2019.105248] [PMID: 31676458]

[47]
Narayan P, Osgood CL, Singh H, et al. FDA approval summary: Fam-trastuzumab deruxtecan-Nxki for the treatment of unresectable or metastatic HER2-positive breast cancer. Clin Cancer Res  2021; 27(16): 4478-85.
 [http://dx.doi.org/10.1158/1078-0432.CCR-20-4557] [PMID: 33753456]

[48]
Ryan Q, Ibrahim A, Cohen MH, et al. FDA drug approval summary: Lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist  2008; 13(10): 1114-9.
 [http://dx.doi.org/10.1634/theoncologist.2008-0816] [PMID: 18849320]

[49]
Medina P, Goodin S. Lapatinib: A dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther  2008; 30(8): 1426-47.
 [http://dx.doi.org/10.1016/j.clinthera.2008.08.008] [PMID: 18803986]

[50]
Xuhong J-C, Qi X-W, Zhang Y, Jiang J. Mechanism, safety and efficacy of three tyrosine kinase inhibitors lapatinib, neratinib and pyrotinib in HER2-positive breast cancer. Am J Cancer Res  2019; 9: 2103-19.

[51]
Dungo RT, Keating GM. Afatinib: First global approval. Drugs  2013; 73(13): 1503-15.
 [http://dx.doi.org/10.1007/s40265-013-0111-6] [PMID: 23982599]

[52]
Lu X, Liu S, Han M, et al. Afatinib-loaded immunoliposomes functionalized with cetuximab: A novel strategy targeting the epidermal growth factor receptor for treatment of non-small-cell lung cancer. Int J Pharm  2019; 560: 126-35.
 [http://dx.doi.org/10.1016/j.ijpharm.2019.02.001] [PMID: 30742982]

[53]
Lee A. Tucatinib: First approval. Drugs  2020; 80(10): 1033-8.
 [http://dx.doi.org/10.1007/s40265-020-01340-w] [PMID: 32548668]

[54]
Shah M, Wedam S, Cheng J, et al. FDA approval summary: Tucatinib for the treatment of patients with advanced or metastatic HER2-positive breast cancer. Clin Cancer Res  2021; 27(5): 1220-6.
 [http://dx.doi.org/10.1158/1078-0432.CCR-20-2701] [PMID: 33055172]

[55]
Ulrich L, Okines AFC. Treating advanced unresectable or metastatic HER2-positive breast cancer: A spotlight on tucatinib. Breast Cancer  2021; 13: 361-81.
 [http://dx.doi.org/10.2147/BCTT.S268451] [PMID: 34079368]

[56]
Ni J, Wang Y, Diala I, et al. Abstract 4832: Preclinical evaluation of neratinib plus T-DM1 in orthotopic PDX models of HER2-positive breast cancer brain metastases. Exp Mol Ther  2019; 79(S13): 4832-2.
 [http://dx.doi.org/10.1158/1538-7445.AM2019-4832]

[57]
Zhao M, Scott S, Evans KW, et al. Combining neratinib with CDK4/6, mTOR, and MEK inhibitors in models of HER2-positive Cancer. Clin Cancer Res  2021; 27(6): 1681-94.
 [http://dx.doi.org/10.1158/1078-0432.CCR-20-3017] [PMID: 33414137]

[58]
Li X, Yang C, Wan H, et al. Discovery and development of pyrotinib: A novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer. Eur J Pharm Sci  2017; 110: 51-61.
 [http://dx.doi.org/10.1016/j.ejps.2017.01.021] [PMID: 28115222]

[59]
Xu B, Yan M, Ma F, et al. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): A multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol  2021; 22(3): 351-60.
 [http://dx.doi.org/10.1016/S1470-2045(20)30702-6] [PMID: 33581774]

[60]
Cai X, Zhai HX, Wang J, et al. Discovery of 7-(4-(3-ethynyl-phenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptan-amide (CUDc-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J Med Chem  2010; 53(5): 2000-9.
 [http://dx.doi.org/10.1021/jm901453q] [PMID: 20143778]

[61]
Shimizu T, LoRusso PM, Papadopoulos KP, et al. Phase I first-in-human study of CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 in patients with advanced solid tumors. Clin Cancer Res  2014; 20(19): 5032-40.
 [http://dx.doi.org/10.1158/1078-0432.CCR-14-0570] [PMID: 25107918]

[62]
Lane CA, Hardy J, Schott JM. Alzheimer’s disease. Eur J Neurol  2018; 25(1): 59-70.
 [http://dx.doi.org/10.1111/ene.13439] [PMID: 28872215]

[63]
Mahboobi S, Sellmer A, Winkler M, et al. Novel chimeric histone deacetylase inhibitors: A series of lapatinib hybrides as potent inhibitors of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and histone deacetylase activity. J Med Chem  2010; 53(24): 8546-55.
 [http://dx.doi.org/10.1021/jm100665z] [PMID: 21080629]

[64]
Elwaie TA, Abbas SE, Aly EI, et al. HER2 kinase-targeted breast cancer therapy: design, synthesis, and in vitro and in vivo evaluation of novel lapatinib congeners as selective and potent HER2 inhibitors with favorable metabolic stability. J Med Chem  2020; 63(24): 15906-45.
 [http://dx.doi.org/10.1021/acs.jmedchem.0c01647] [PMID: 33314925]

[65]
Zhang L, Fan C, Guo Z, et al. Discovery of a potent dual EGFR/HER-2 inhibitor L-2 (selatinib) for the treatment of cancer. Eur J Med Chem  2013; 69: 833-41.
 [http://dx.doi.org/10.1016/j.ejmech.2013.09.032] [PMID: 24121234]

[66]
Elkamhawy A, Farag AK, Viswanath ANI, et al. Targeting EGFR/HER2 tyrosine kinases with a new potent series of 6-substituted 4-anilinoquinazoline hybrids: Design, synthesis, kinase assay, cell-based assay, and molecular docking. Bioorg Med Chem Lett  2015; 25(22): 5147-54.
 [http://dx.doi.org/10.1016/j.bmcl.2015.10.003] [PMID: 26475520]

[67]
Lyu A, Fang L, Gou S. Design and synthesis of Lapatinib derivatives containing a branched side chain as HER1/HER2 targeting antitumor drug candidates. Eur J Med Chem  2014; 87: 631-42.
 [http://dx.doi.org/10.1016/j.ejmech.2014.10.006] [PMID: 25305330]

[68]
Sadek MM, Serrya RA, Kafafy AHN, Ahmed M, Wang F, Abouzid KAM. Discovery of new HER2/EGFR dual kinase inhibitors based on the anilinoquinazoline scaffold as potential anti-cancer agents. J Enzyme Inhib Med Chem  2014; 29(2): 215-22.
 [http://dx.doi.org/10.3109/14756366.2013.765417] [PMID: 23402383]

[69]
Sun M, Jia J, Sun H, Wang F. Design and synthesis of a novel class EGFR/HER2 dual inhibitors containing tricyclic oxazine fused quinazolines scaffold. Bioorg Med Chem Lett  2020; 30(9): 127045.
 [http://dx.doi.org/10.1016/j.bmcl.2020.127045] [PMID: 32139324]

[70]
Yin S, Tang C, Wang B, et al. Design, synthesis and biological evaluation of novel EGFR/HER2 dual inhibitors bearing a oxazolo[4,5-g]quinazolin-2(1H)-one scaffold. Eur J Med Chem  2016; 120: 26-36.
 [http://dx.doi.org/10.1016/j.ejmech.2016.04.072] [PMID: 27187856]

[71]
Alkahtani HM, Abdalla AN, Obaidullah AJ, et al. Synthesis, cytotoxic evaluation, and molecular docking studies of novel quinazoline derivatives with benzenesulfonamide and anilide tails: Dual inhibitors of EGFR/HER2. Bioorg Chem  2020; 95: 103461.
 [http://dx.doi.org/10.1016/j.bioorg.2019.103461] [PMID: 31838290]

[72]
Soliman AM, Alqahtani AS, Ghorab MM. Novel sulfonamide benzoquinazolinones as dual EGFR/HER2 inhibitors, apoptosis inducers and radiosensitizers. J Enzyme Inhib Med Chem  2019; 34(1): 1030-40.
 [http://dx.doi.org/10.1080/14756366.2019.1609469] [PMID: 31074303]

[73]
Alsaid MS, Al-Mishari AA, Soliman AM, Ragab FA, Ghorab MM. Discovery of Benzo[g]quinazolin benzenesulfonamide derivatives as dual EGFR/HER2 inhibitors. Eur J Med Chem  2017; 141: 84-91.
 [http://dx.doi.org/10.1016/j.ejmech.2017.09.061] [PMID: 29028534]

[74]
Ghorab MM, Alsaid MS, Soliman AM. Dual EGFR/HER2 inhibitors and apoptosis inducers: New benzo[g]quinazoline derivatives bearing benzenesulfonamide as anticancer and radiosensitizers. Bioorg Chem  2018; 80: 611-20.
 [http://dx.doi.org/10.1016/j.bioorg.2018.07.015] [PMID: 30041137]

[75]
Wissner A, Overbeek E, Reich MF, et al. Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2). J Med Chem  2003; 46(1): 49-63.
 [http://dx.doi.org/10.1021/jm020241c] [PMID: 12502359]

[76]
Sangani CB, Makawana JA, Duan YT, et al. Design, synthesis and molecular modeling of biquinoline-pyridine hybrids as a new class of potential EGFR and HER-2 kinase inhibitors. Bioorg Med Chem Lett  2014; 24(18): 4472-6.
 [http://dx.doi.org/10.1016/j.bmcl.2014.07.094] [PMID: 25172421]

[77]
Nguyen CT, Thanh La M, Ann J, et al. Discovery of a simplified deguelin analog as an HSP90 C-terminal inhibitor for HER2-positive breast cancer. Bioorg Med Chem Lett  2021; 45: 128134.
 [http://dx.doi.org/10.1016/j.bmcl.2021.128134] [PMID: 34044120]

[78]
Abdellatif KRA, Belal A, El-Saadi MT, Amin NH, Said EG, Hemeda LR. Design, synthesis, molecular docking and antiproliferative activity of some novel benzothiazole derivatives targeting EGFR/HER2 and TS. Bioorg Chem  2020; 101: 103976.
 [http://dx.doi.org/10.1016/j.bioorg.2020.103976] [PMID: 32506018]

[79]
Hughes TV, Xu G, Wetter SK, et al. A novel 5-[1,3,4-oxadiazol-2-yl]-N-aryl-4,6-pyrimidine diamine having dual EGFR/HER2 kinase activity: Design, synthesis, and biological activity. Bioorg Med Chem Lett  2008; 18(17): 4896-9.
 [http://dx.doi.org/10.1016/j.bmcl.2008.07.057] [PMID: 18678484]

[80]
Suzuki N, Shiota T, Watanabe F, et al. Synthesis and evaluation of novel pyrimidine-based dual EGFR/HER-2 inhibitors. Bioorg Med Chem Lett  2011; 21(6): 1601-6.
 [http://dx.doi.org/10.1016/j.bmcl.2011.01.119] [PMID: 21334203]

[81]
Cha MY, Lee KO, Kang SJ, et al. Synthesis and biological evaluation of pyrimidine-based dual inhibitors of human epidermal growth factor receptor 1 (HER-1) and HER-2 tyrosine kinases. J Med Chem  2012; 55(6): 2846-57.
 [http://dx.doi.org/10.1021/jm201758g] [PMID: 22372864]

[82]
Milik SN, Abdel-Aziz AK, Lasheen DS, Serya RAT, Minucci S, Abouzid KAM. Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors. Eur J Med Chem  2018; 155: 316-36.
 [http://dx.doi.org/10.1016/j.ejmech.2018.06.011] [PMID: 29902719]

[83]
Lippa B, Kauffman GS, Arcari J, et al. The discovery of highly selective erbB2 (HER2) inhibitors for the treatment of cancer. Bioorg Med Chem Lett  2007; 17(11): 3081-6.
 [http://dx.doi.org/10.1016/j.bmcl.2007.03.046] [PMID: 17398092]

[84]
Chiosis G, Lucas B, Shtil A, Huezo H, Rosen N. Development of a purine-scaffold novel class of Hsp90 binders that inhibit the proliferation of cancer cells and induce the degradation of HER2 tyrosine kinase. Bioorg Med Chem  2002; 10(11): 3555-64.
 [http://dx.doi.org/10.1016/S0968-0896(02)00253-5] [PMID: 12213470]

[85]
Elmetwally SA, Saied KF, Eissa IH, Elkaeed EB. Design, synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers. Bioorg Chem  2019; 88: 102944.
 [http://dx.doi.org/10.1016/j.bioorg.2019.102944] [PMID: 31051400]

[86]
Kawakita Y, Seto M, Ohashi T, et al. Design and synthesis of novel pyrimido[4,5-b]azepine derivatives as HER2/EGFR dual inhibitors. Bioorg Med Chem  2013; 21(8): 2250-61.
 [http://dx.doi.org/10.1016/j.bmc.2013.02.014] [PMID: 23490150]

[87]
Kawakita Y, Banno H, Ohashi T, et al. Design and synthesis of pyrrolo[3,2-d]pyrimidine human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors: Exploration of novel back-pocket binders. J Med Chem  2012; 55(8): 3975-91.
 [http://dx.doi.org/10.1021/jm300185p] [PMID: 22439974]

[88]
Lamie PF, El-Kalaawy AM, Abdel Latif NS, Rashed LA, Philoppes JN. Pyrazolo[3,4-d]pyrimidine-based dual EGFR T790M/HER2 inhibitors: Design, synthesis, structure-activity relationship and biological activity as potential antitumor and anticonvulsant agents. Eur J Med Chem  2021; 214: 113222.
 [http://dx.doi.org/10.1016/j.ejmech.2021.113222] [PMID: 33545637]

[89]
Kawakita Y, Miwa K, Seto M, et al. Design and synthesis of pyrrolo[3,2-d]pyrimidine HER2/EGFR dual inhibitors: Improvement of the physicochemical and pharmacokinetic profiles for potent in vivo anti-tumor efficacy. Bioorg Med Chem  2012; 20(20): 6171-80.
 [http://dx.doi.org/10.1016/j.bmc.2012.08.002] [PMID: 22980219]

[90]
Abd El Hadi SR, Lasheen DS, Hassan MA, Abouzid KAM. Design and synthesis of 4‐anilinothieno[2,3‐d]pyrimidine‐based compounds as dual EGFR/HER‐2 inhibitors. Arch Pharm  2016; 349(11): 827-47.
 [http://dx.doi.org/10.1002/ardp.201600197] [PMID: 27734525]

[91]
Ishikawa T, Seto M, Banno H, et al. Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold. J Med Chem  2011; 54(23): 8030-50.
 [http://dx.doi.org/10.1021/jm2008634] [PMID: 22003817]

[92]
Cruz-López O, Ner M, Nerín-Fonz F, et al. Design, synthesis, HER2 inhibition and anticancer evaluation of new substituted 1,5-dihydro-4,1-benzoxazepines. J Enzyme Inhib Med Chem  2021; 36(1): 1551-61.
 [http://dx.doi.org/10.1080/14756366.2021.1948841] [PMID: 34251942]

[93]
Elrayess R, Abdel Aziz YM, Elgawish MS, et al. Discovery of potent dual EGFR/HER2 inhibitors based on thiophene scaffold targeting H1299 lung cancer cell line. Pharmaceuticals  2020; 14(1): 9.
 [http://dx.doi.org/10.3390/ph14010009] [PMID: 33374155]

[94]
Sever B. Altıntop MD, Radwan MO, et al. Design, synthesis and biological evaluation of a new series of thiazolyl-pyrazolines as dual EGFR and HER2 inhibitors. Eur J Med Chem  2019; 182: 111648.
 [http://dx.doi.org/10.1016/j.ejmech.2019.111648] [PMID: 31493743]

[95]
Qiu KM, Wang HH, Wang LM, et al. Design, synthesis and biological evaluation of pyrazolyl-thiazolinone derivatives as potential EGFR and HER-2 kinase inhibitors. Bioorg Med Chem  2012; 20(6): 2010-8.
 [http://dx.doi.org/10.1016/j.bmc.2012.01.051] [PMID: 22361272]

[96]
Tao XX, Duan YT, Chen LW, et al. Design, synthesis and biological evaluation of pyrazolyl-nitroimidazole derivatives as potential EGFR/HER-2 kinase inhibitors. Bioorg Med Chem Lett  2016; 26(2): 677-83.
 [http://dx.doi.org/10.1016/j.bmcl.2015.11.040] [PMID: 26652482]

[97]
Qian Y, Zhang HJ, Zhang H, Xu C, Zhao J, Zhu HL. Synthesis, molecular modeling, and biological evaluation of cinnamic acid metronidazole ester derivatives as novel anticancer agents. Bioorg Med Chem  2010; 18(14): 4991-6.
 [http://dx.doi.org/10.1016/j.bmc.2010.06.003] [PMID: 20594859]

[98]
Lv PC, Zhou CF, Chen J, et al. Design, synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors. Bioorg Med Chem  2010; 18(1): 314-9.
 [http://dx.doi.org/10.1016/j.bmc.2009.10.051] [PMID: 19914835]

[99]
Cheng ZY, Li WJ, He F, Zhou JM, Zhu XF. Synthesis and biological evaluation of 4-aryl-5-cyano-2H-1,2,3-triazoles as inhibitor of HER2 tyrosine kinase. Bioorg Med Chem  2007; 15(3): 1533-8.
 [http://dx.doi.org/10.1016/j.bmc.2006.09.041] [PMID: 17174554]

[100]
Li HQ, Yan T, Yang Y, Shi L, Zhou CF, Zhu HL. Synthesis and structure-activity relationships of N-benzyl-N-(X-2-hydroxybenzyl)-N′-phenylureas and thioureas as antitumor agents. Bioorg Med Chem  2010; 18(1): 305-13.
 [http://dx.doi.org/10.1016/j.bmc.2009.10.054] [PMID: 19914837]

[101]
Satyanarayanajois S, Villalba S, Jianchao L, Lin GM. Design, synthesis, and docking studies of peptidomimetics based on HER2-herceptin binding site with potential antiproliferative activity against breast cancer cell lines. Chem Biol Drug Des  2009; 74(3): 246-57.
 [http://dx.doi.org/10.1111/j.1747-0285.2009.00855.x] [PMID: 19703026]

[102]
Li J, Wang H, Li J, Bao J, Wu C. Discovery of a potential HER2 inhibitor from natural products for the treatment of HER2-positive breast cancer. Int J Mol Sci  2016; 17(7): 1055.
 [http://dx.doi.org/10.3390/ijms17071055] [PMID: 27376283]

[103]
Labib MB, Philoppes JN, Lamie PF, Ahmed ER. Azole-hydrazone derivatives: Design, synthesis, in vitro biological evaluation, dual EGFR/HER2 inhibitory activity, cell cycle analysis and molecular docking study as anticancer agents. Bioorg Chem  2018; 76: 67-80.
 [http://dx.doi.org/10.1016/j.bioorg.2017.10.016] [PMID: 29153588]

[104]
Elseginy SA, Hamdy R, Menon V, Almehdi AM, El-Awady R, Soliman SSM. Design, synthesis, and computational validation of novel compounds selectively targeting HER2-expressing breast cancer. Bioorg Med Chem Lett  2020; 30(24): 127658.
 [http://dx.doi.org/10.1016/j.bmcl.2020.127658] [PMID: 33130288]

[105]
Zhao A, Zheng Q, Orahoske CM, et al. Synthesis and biological evaluation of anti-cancer agents that selectively inhibit HER2 over-expressed breast cancer cell growth via down-regulation of HER2 protein. Bioorg Med Chem Lett  2018; 28(4): 727-31.
 [http://dx.doi.org/10.1016/j.bmcl.2018.01.016] [PMID: 29352646]
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DOI https://dx.doi.org/10.2174/0113816128283615231218094706	Print ISSN 1381-6128
Publisher Name Bentham Science Publisher	Online ISSN 1873-4286
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