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Development of Specific, Irreversible Inhibitors for a Receptor Tyrosine Kinase EphB3.

Kung A, Chen YC, Schimpl M, Ni F, Zhu J, Turner M, Molina H, Overman R, Zhang C
J Am Chem Soc 138 10554-60 (2016)
Cited: 16 times
EuropePMC logo PMID: 27478969

Abstract

Erythropoietin-producing human hepatocellular carcinoma (Eph) receptor tyrosine kinases (RTKs) regulate a variety of dynamic cellular events, including cell protrusion, migration, proliferation, and cell-fate determination. Small-molecule inhibitors of Eph kinases are valuable tools for dissecting the physiological and pathological roles of Eph. However, there is a lack of small-molecule inhibitors that are selective for individual Eph isoforms due to the high homology within the family. Herein, we report the development of the first potent and specific inhibitors of a single Eph isoform, EphB3. Through structural bioinformatic analysis, we identified a cysteine in the hinge region of the EphB3 kinase domain, a feature that is not shared with any other human kinases. We synthesized and characterized a series of electrophilic quinazolines to target this unique, reactive feature in EphB3. Some of the electrophilic quinazolines selectively and potently inhibited EphB3 both in vitro and in cells. Cocrystal structures of EphB3 in complex with two quinazolines confirmed the covalent linkage between the protein and the inhibitors. A "clickable" version of an optimized inhibitor was created and employed to verify specific target engagement in the whole proteome and to probe the extent and kinetics of target engagement of existing EphB3 inhibitors. Furthermore, we demonstrate that the autophosphorylation of EphB3 within the juxtamembrane region occurs in trans using a specific inhibitor. These exquisitely specific inhibitors will facilitate the dissection of EphB3's role in various biological processes and disease contribution.

Articles - 5l6p mentioned but not cited (2)

  1. An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mpro inhibitor. Zaidman D, Gehrtz P, Filep M, Fearon D, Gabizon R, Douangamath A, Prilusky J, Duberstein S, Cohen G, Owen CD, Resnick E, Strain-Damerell C, Lukacik P, Covid-Moonshot Consortium, Barr H, Walsh MA, von Delft F, London N. Cell Chem Biol 28 1795-1806.e5 (2021)
  2. Hit Identification of a Novel Quinazoline Sulfonamide as a Promising EphB3 Inhibitor: Design, Virtual Combinatorial Library, Synthesis, Biological Evaluation, and Docking Simulation Studies. Lee K, Nada H, Byun HJ, Lee CH, Elkamhawy A. Pharmaceuticals (Basel) 14 1247 (2021)


Reviews citing this publication (4)

  1. The Cysteinome of Protein Kinases as a Target in Drug Development. Chaikuad A, Koch P, Laufer SA, Knapp S. Angew Chem Int Ed Engl 57 4372-4385 (2018)
  2. Pseudokinases: update on their functions and evaluation as new drug targets. Byrne DP, Foulkes DM, Eyers PA. Future Med Chem 9 245-265 (2017)
  3. Eph receptors and ephrins in cancer progression. Pasquale EB. Nat Rev Cancer 24 5-27 (2024)
  4. Reactivity-based chemical-genetic study of protein kinases. Rezende Miranda R, Zhang C. RSC Med Chem 13 783-797 (2022)

Articles citing this publication (10)

  1. Barcoded viral tracing of single-cell interactions in central nervous system inflammation. Clark IC, Gutiérrez-Vázquez C, Wheeler MA, Li Z, Rothhammer V, Linnerbauer M, Sanmarco LM, Guo L, Blain M, Zandee SEJ, Chao CC, Batterman KV, Schwabenland M, Lotfy P, Tejeda-Velarde A, Hewson P, Manganeli Polonio C, Shultis MW, Salem Y, Tjon EC, Fonseca-Castro PH, Borucki DM, Alves de Lima K, Plasencia A, Abate AR, Rosene DL, Hodgetts KJ, Prinz M, Antel JP, Prat A, Quintana FJ. Science 372 eabf1230 (2021)
  2. Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases. Sheetz JB, Mathea S, Karvonen H, Malhotra K, Chatterjee D, Niininen W, Perttilä R, Preuss F, Suresh K, Stayrook SE, Tsutsui Y, Radhakrishnan R, Ungureanu D, Knapp S, Lemmon MA. Mol Cell 79 390-405.e7 (2020)
  3. Expanding the Arsenal of FGFR Inhibitors: A Novel Chloroacetamide Derivative as a New Irreversible Agent With Anti-proliferative Activity Against FGFR1-Amplified Lung Cancer Cell Lines. Fumarola C, Bozza N, Castelli R, Ferlenghi F, Marseglia G, Lodola A, Bonelli M, La Monica S, Cretella D, Alfieri R, Minari R, Galetti M, Tiseo M, Ardizzoni A, Mor M, Petronini PG. Front Oncol 9 179 (2019)
  4. Using Protein-Confined Proximity To Determine Chemical Reactivity. Kobayashi T, Hoppmann C, Yang B, Wang L. J Am Chem Soc 138 14832-14835 (2016)
  5. Covalent Modulators of the Vacuolar ATPase. Chen YC, Backus KM, Merkulova M, Yang C, Brown D, Cravatt BF, Zhang C. J Am Chem Soc 139 639-642 (2017)
  6. Characterization of FGF401 as a reversible covalent inhibitor of fibroblast growth factor receptor 4. Zhou Z, Chen X, Fu Y, Zhang Y, Dai S, Li J, Chen L, Xu G, Chen Z, Chen Y. Chem Commun (Camb) 55 5890-5893 (2019)
  7. A Chemical-Genetic Approach to Generate Selective Covalent Inhibitors of Protein Kinases. Kung A, Schimpl M, Ekanayake A, Chen YC, Overman R, Zhang C. ACS Chem Biol 12 1499-1503 (2017)
  8. Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain. Ahmed MS, Wang P, Nguyen NUN, Nakada Y, Menendez-Montes I, Ismail M, Bachoo R, Henkemeyer M, Sadek HA, Kandil ES. Proc Natl Acad Sci U S A 118 e2016265118 (2021)
  9. Rigidification Dramatically Improves Inhibitor Selectivity for RAF Kinases. Assadieskandar A, Yu C, Maisonneuve P, Kurinov I, Sicheri F, Zhang C. ACS Med Chem Lett 10 1074-1080 (2019)
  10. Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester. Castro-Falcón G, Seiler GS, Demir Ö, Rathinaswamy MK, Hamelin D, Hoffmann RM, Makowski SL, Letzel AC, Field SJ, Burke JE, Amaro RE, Hughes CC. J Med Chem 61 10463-10472 (2018)


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