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Design and synthesis of novel pyrimido[4,5-b]azepine derivatives as HER2/EGFR dual inhibitors.

Kawakita Y, Seto M, Ohashi T, Tamura T, Yusa T, Miki H, Iwata H, Kamiguchi H, Tanaka T, Sogabe S, Ohta Y, Ishikawa T
Bioorg Med Chem 21 2250-2261 (2013)
Cited: 25 times
EuropePMC logo PMID: 23490150

Abstract

A novel 7,6 fused bicyclic scaffold, pyrimido[4,5-b]azepine was designed to fit into the ATP binding site of the HER2/EGFR proteins. The synthesis of this scaffold was accomplished by an intramolecular Claisen-type condensation. As the results of optimization lead us to 4-anilino and 6-functional groups, we discovered 6-substituted amide derivative 19b, which has a 1-benzothiophen-4-yloxy group attached to the 4-anilino group. An X-ray co-crystal structure of 19b with EGFR demonstrated that the N-1 and N-3 nitrogens of the pyrimido[4,5-b]azepine scaffold make hydrogen-bonding interactions with the main chain NH of Met793 and the side chain of Thr854 via a water-mediated hydrogen bond network, respectively. In addition, the NH proton at the 9-position makes an additional hydrogen bond with the carbonyl group of Met793, as we expected. Compound 19b revealed potent HER2/EGFR kinase (IC50: 24/36 nM) and BT474 cell growth (GI50: 18 nM) inhibitory activities based on its pseudo-irreversible (PI) profile.

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  1. Novel Adamantanyl-Based Thiadiazolyl Pyrazoles Targeting EGFR in Triple-Negative Breast Cancer. Sebastian A, Pandey V, Mohan CD, Chia YT, Rangappa S, Mathai J, Baburajeev CP, Paricharak S, Mervin LH, Bulusu KC, Fuchs JE, Bender A, Yamada S, Basappa, Lobie PE, Rangappa KS. ACS Omega 1 1412-1424 (2016)
  2. Inspiration for COVID-19 Treatment: Network Analysis and Experimental Validation of Baicalin for Cytokine Storm. You J, Li H, Fan P, Yang X, Wei Y, Zheng L, Li Z, Yi C. Front Pharmacol 13 853496 (2022)
  3. Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase. Kurup S, McAllister B, Liskova P, Mistry T, Fanizza A, Stanford D, Slawska J, Keller U, Hoellein A. J Enzyme Inhib Med Chem 33 74-84 (2018)
  4. Anti-Cancer Effects of an Optimised Combination of Ginsenoside Rg3 Epimers on Triple Negative Breast Cancer Models. Nakhjavani M, Smith E, Palethorpe HM, Tomita Y, Yeo K, Price TJ, Townsend AR, Hardingham JE. Pharmaceuticals (Basel) 14 633 (2021)
  5. Navigating into the binding pockets of the HER family protein kinases: discovery of novel EGFR inhibitor as antitumor agent. Liu W, Ning JF, Meng QW, Hu J, Zhao YB, Liu C, Cai L. Drug Des Devel Ther 9 3837-3851 (2015)
  6. Statistical analysis of EGFR structures' performance in virtual screening. Li Y, Li X, Dong Z. J Comput Aided Mol Des 29 1045-1055 (2015)
  7. Synthesis, Molecular Docking Study, and Cytotoxicity Evaluation of Some Novel 1,3,4-Thiadiazole as Well as 1,3-Thiazole Derivatives Bearing a Pyridine Moiety. Abouzied AS, Al-Humaidi JY, Bazaid AS, Qanash H, Binsaleh NK, Alamri A, Ibrahim SM, Gomha SM. Molecules 27 6368 (2022)
  8. Effect of Binding Pose and Modeled Structures on SVMGen and GlideScore Enrichment of Chemical Libraries. Xu D, Meroueh SO. J Chem Inf Model 56 1139-1151 (2016)
  9. Computer-Aided Screening and Revealing Action Mechanism of Food-Derived Tripeptides Intervention in Acute Colitis. Ge H, Zhang T, Tang Y, Zhang Y, Yu Y, Men F, Liu J, Yu Y. Int J Mol Sci 23 13471 (2022)
  10. Identification of afzelin potential targets in inhibiting triple-negative breast cancer cell migration using reverse docking. Rachmi E, Purnomo BB, Endharti AT, Fitri LE. Porto Biomed J 5 e095 (2020)
  11. Synthesis, Biological Evaluation, and Molecular Docking of Novel Azolylhydrazonothiazoles as Potential Anticancer Agents. Al-Humaidi JY, Gomha SM, Riyadh SM, Ibrahim MS, Zaki MEA, Abolibda TZ, Jefri OA, Abouzied AS. ACS Omega 8 34044-34058 (2023)


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  1. Small molecule tyrosine kinase inhibitors of ErbB2/HER2/Neu in the treatment of aggressive breast cancer. Schroeder RL, Stevens CL, Sridhar J. Molecules 19 15196-15212 (2014)
  2. How to train your inhibitor: Design strategies to overcome resistance to Epidermal Growth Factor Receptor inhibitors. Milik SN, Lasheen DS, Serya RAT, Abouzid KAM. Eur J Med Chem 142 131-151 (2017)

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  1. Altered conformational landscape and dimerization dependency underpins the activation of EGFR by αC-β4 loop insertion mutations. Ruan Z, Kannan N. Proc Natl Acad Sci U S A 115 E8162-E8171 (2018)
  2. Inhibiting epidermal growth factor receptor signalling potentiates mesenchymal-epithelial transition of breast cancer stem cells and their responsiveness to anticancer drugs. Manupati K, Dhoke NR, Debnath T, Yeeravalli R, Guguloth K, Saeidpour S, De UC, Debnath S, Das A. FEBS J 284 1830-1854 (2017)
  3. Synthesis, biological evaluation and molecular docking studies of pyrazole derivatives coupling with a thiourea moiety as novel CDKs inhibitors. Sun J, Lv XH, Qiu HY, Wang YT, Du QR, Li DD, Yang YH, Zhu HL. Eur J Med Chem 68 1-9 (2013)
  4. Computational and Experimental Characterization of Patient Derived Mutations Reveal an Unusual Mode of Regulatory Spine Assembly and Drug Sensitivity in EGFR Kinase. Ruan Z, Katiyar S, Kannan N. Biochemistry 56 22-32 (2017)
  5. Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death. Iradyan M, Iradyan N, Hulin P, Hambardzumyan A, Gyulkhandanyan A, Alves de Sousa R, Hessani A, Roussakis C, Bollot G, Bauvais C, Sakanyan V. Cancers (Basel) 11 E1094 (2019)
  6. Conformational transition paths harbor structures useful for aiding drug discovery and understanding enzymatic mechanisms in protein kinases. Wong CF. Protein Sci 25 192-203 (2016)
  7. Structure-Activity Relationships of Hexahydrocyclopenta[c]quinoline Derivatives as Allosteric Inhibitors of CDK2 and EGFR. Carlino L, Christodoulou MS, Restelli V, Caporuscio F, Foschi F, Semrau MS, Costanzi E, Tinivella A, Pinzi L, Lo Presti L, Battistutta R, Storici P, Broggini M, Passarella D, Rastelli G. ChemMedChem 13 2627-2634 (2018)
  8. SAR and QSAR study on the bioactivities of human epidermal growth factor receptor-2 (HER2) inhibitors. Qu D, Yan A, Zhang JS. SAR QSAR Environ Res 28 111-132 (2017)
  9. TeachOpenCADD 2022: open source and FAIR Python pipelines to assist in structural bioinformatics and cheminformatics research. Sydow D, Rodríguez-Guerra J, Kimber TB, Schaller D, Taylor CJ, Chen Y, Leja M, Misra S, Wichmann M, Ariamajd A, Volkamer A. Nucleic Acids Res 50 W753-W760 (2022)
  10. Reckoning apigenin and kaempferol as a potential multi-targeted inhibitor of EGFR/HER2-MEK pathway of metastatic colorectal cancer identified using rigorous computational workflow. Sharma A, Sinha S, Rathaur P, Vora J, Jha PC, Johar K, Rawal RM, Shrivastava N. Mol Divers 26 3337-3356 (2022)
  11. Stereocontrolled addition of Grignard reagents to oxa-bridged benzazepines: highly efficient synthesis of functionalized benzazepine scaffolds. Zhang Y, Bao Q, Zhang N, Wang S, Yu X. RSC Adv 10 41802-41806 (2020)


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