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Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study.

Heald R, Bowman KK, Bryan MC, Burdick D, Chan B, Chan E, Chen Y, Clausen S, Dominguez-Fernandez B, Eigenbrot C, Elliott R, Hanan EJ, Jackson P, Knight J, La H, Lainchbury M, Malek S, Mann S, Merchant M, Mortara K, Purkey H, Schaefer G, Schmidt S, Seward E, Sideris S, Shao L, Wang S, Yeap K, Yen I, Yu C, Heffron TP
J Med Chem 58 8877-95 (2015)
Related entries: 5c8k, 5c8m, 5c8n, 5cal, 5can, 5cao, 5cap, 5cas, 5cau, 5cav

Cited: 18 times
EuropePMC logo PMID: 26455919

Abstract

Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.

Articles - 5caq mentioned but not cited (1)

  1. Molecular Docking Optimization in the Context of Multi-Drug Resistant and Sensitive EGFR Mutants. García-Godoy MJ, López-Camacho E, García-Nieto J, Nebro AJ, Aldana-Montes JF. Molecules 21 E1575 (2016)


Reviews citing this publication (3)

  1. Targeting EGFRL858R/T790M and EGFRL858R/T790M/C797S resistance mutations in NSCLC: Current developments in medicinal chemistry. Lu X, Yu L, Zhang Z, Ren X, Smaill JB, Ding K. Med Res Rev 38 1550-1581 (2018)
  2. Recent Advances in the Development and Application of Radiolabeled Kinase Inhibitors for PET Imaging. Bernard-Gauthier V, Bailey JJ, Berke S, Schirrmacher R. Molecules 20 22000-22027 (2015)
  3. The "Sticky Patch" Model of Crystallization and Modification of Proteins for Enhanced Crystallizability. Derewenda ZS, Godzik A. Methods Mol Biol 1607 77-115 (2017)

Articles citing this publication (14)

  1. Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer. Eno MS, Brubaker JD, Campbell JE, De Savi C, Guzi TJ, Williams BD, Wilson D, Wilson K, Brooijmans N, Kim J, Özen A, Perola E, Hsieh J, Brown V, Fetalvero K, Garner A, Zhang Z, Stevison F, Woessner R, Singh J, Timsit Y, Kinkema C, Medendorp C, Lee C, Albayya F, Zalutskaya A, Schalm S, Dineen TA. J Med Chem 65 9662-9677 (2022)
  2. The marine-derived pachycladin diterpenoids as novel inhibitors of wild-type and mutant EGFR. Mohyeldin MM, Akl MR, Siddique AB, Hassan HM, El Sayed KA. Biochem Pharmacol 126 51-68 (2017)
  3. Design, synthesis, SAR discussion, in vitro and in vivo evaluation of novel selective EGFR modulator to inhibit L858R/T790M double mutants. Zhang H, Wu W, Feng C, Liu Z, Bai E, Wang X, Lei M, Cheng H, Feng H, Shi J, Wang J, Zhang Z, Jin T, Chen S, Hu S, Zhu Y. Eur J Med Chem 135 12-23 (2017)
  4. Design and Synthesis of Non-Covalent Imidazo[1,2-a]quinoxaline-Based Inhibitors of EGFR and Their Anti-Cancer Assessment. Kumar M, Joshi G, Arora S, Singh T, Biswas S, Sharma N, Bhat ZR, Tikoo K, Singh S, Kumar R. Molecules 26 1490 (2021)
  5. How Far Are We from the Rapid Prediction of Drug Resistance Arising Due to Kinase Mutations? Erguven M, Karakulak T, Diril MK, Karaca E. ACS Omega 6 1254-1265 (2021)
  6. Identification of antiproliferative emodin analogues as inhibitors of epidermal growth factor receptor in cancer. Chen KC, Juang SH, Lien JC. Int J Mol Med 43 1281-1288 (2019)
  7. Triple targeting of mutant EGFRL858R/T790M, COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation. Kothayer H, Rezq S, Abdelkhalek AS, Romero DG, Elbaramawi SS. J Enzyme Inhib Med Chem 38 2199166 (2023)
  8. A systematic pipeline of protein structure selection for computer-aided drug discovery: A case study on T790M/L858R mutant EGFR structures. Das AP, Nandekar P, Mathur P, Agarwal SM. Protein Sci 32 e4740 (2023)
  9. Design, synthesis and biological evaluation of novel 4-anlinoquinazoline derivatives as EGFR inhibitors with the potential to inhibit the gefitinib-resistant nonsmall cell lung cancers. Wang C, Xu S, Peng L, Zhang B, Zhang H, Hu Y, Zheng P, Zhu W. J Enzyme Inhib Med Chem 34 203-217 (2019)
  10. Discovery of novel quinazoline derivatives bearing semicarbazone moiety as potent EGFR kinase inhibitors. Tu Y, Wang C, Yang Z, Zhao B, Lai L, Yang Q, Zheng P, Zhu W. Comput Struct Biotechnol J 16 462-478 (2018)
  11. Unraveling structural requirements of amino-pyrimidine T790M/L858R double mutant EGFR inhibitors: 2D and 3D QSAR study. Fatima S, Agarwal SM. J Recept Signal Transduct Res 38 299-306 (2018)
  12. Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo. Lai M, Zhang T, Chen H, Song P, Tong L, Chen J, Liu Y, Ning Y, Feng F, Li Y, Tang H, Chen Y, Fang Y, Lu X, Geng M, Ding K, Yu K, Ding J, Xie H. J Cancer 14 152-162 (2023)
  13. Machine Learning, Molecular Docking, and Dynamics-Based Computational Identification of Potential Inhibitors against Lung Cancer. Das AP, Mathur P, Agarwal SM. ACS Omega 9 4528-4539 (2024)
  14. Structural elements that enable specificity for mutant EGFR kinase domains with next-generation small-molecule inhibitors. Damghani T, Wittlinger F, Beyett TS, Eck MJ, Laufer SA, Heppner DE. Methods Enzymol 685 171-198 (2023)


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