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Fragment-based discovery of new highly substituted 1H-pyrrolo[2,3-b]- and 3H-imidazolo[4,5-b]-pyridines as focal adhesion kinase inhibitors.

Heinrich T, Seenisamy J, Emmanuvel L, Kulkarni SS, Bomke J, Rohdich F, Greiner H, Esdar C, Krier M, Grädler U, Musil D
J Med Chem 56 1160-70 (2013)
Cited: 25 times
EuropePMC logo PMID: 23294348

Abstract

Focal adhesion kinase (FAK) is considered as an attractive target for oncology, and small-molecule inhibitors are reported to be in clinical testing. In a surface plasmon resonance (SPR)-mediated fragment screening campaign, we discovered bicyclic scaffolds like 1H-pyrazolo[3,4-d]pyrimidines binding to the hinge region of FAK. By an accelerated knowledge-based fragment growing approach, essential pharmacophores were added. The establishment of highly substituted unprecedented 1H-pyrrolo[2,3-b]pyridine derivatizations provided compounds with submicromolar cellular FAK inhibition potential. The combination of substituents on the bicyclic templates and the nature of the core structure itself have a significant impact on the compounds FAK selectivity. Structural analysis revealed that the appropriately substituted pyrrolo[2,3-b]pyridine induced a rare helical DFG-loop conformation. The discovered synthetic route to introduce three different substituents independently paves the way for versatile applications of the 7-azaindole core.

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  1. Structural protein-ligand interaction fingerprints (SPLIF) for structure-based virtual screening: method and benchmark study. Da C, Kireev D. J Chem Inf Model 54 2555-2561 (2014)


Reviews citing this publication (9)

  1. FAK in cancer: mechanistic findings and clinical applications. Sulzmaier FJ, Jean C, Schlaepfer DD. Nat Rev Cancer 14 598-610 (2014)
  2. Targeting FAK in human cancer: from finding to first clinical trials. Golubovskaya VM. Front Biosci (Landmark Ed) 19 687-706 (2014)
  3. Molecular Pathways: Endothelial Cell FAK-A Target for Cancer Treatment. Roy-Luzarraga M, Hodivala-Dilke K. Clin Cancer Res 22 3718-3724 (2016)
  4. The azaindole framework in the design of kinase inhibitors. Mérour JY, Buron F, Plé K, Bonnet P, Routier S. Molecules 19 19935-19979 (2014)
  5. Endogenous Control Mechanisms of FAK and PYK2 and Their Relevance to Cancer Development. Naser R, Aldehaiman A, Díaz-Galicia E, Arold ST. Cancers (Basel) 10 E196 (2018)
  6. FAK in Cancer: From Mechanisms to Therapeutic Strategies. Chuang HH, Zhen YY, Tsai YC, Chuang CH, Hsiao M, Huang MS, Yang CJ. Int J Mol Sci 23 1726 (2022)
  7. Role of Focal Adhesion Kinase in Small-Cell Lung Cancer and Its Potential as a Therapeutic Target. Aboubakar Nana F, Vanderputten M, Ocak S. Cancers (Basel) 11 E1683 (2019)
  8. FAK inhibitors as promising anticancer targets: present and future directions. Mustafa M, Abd El-Hafeez AA, Abdelhafeez DA, Abdelhamid D, Mostafa YA, Ghosh P, Hayallah AM, A Abuo-Rahma GE. Future Med Chem 13 1559-1590 (2021)
  9. The Hitchhiker's Guide to Deep Learning Driven Generative Chemistry. Ivanenkov Y, Zagribelnyy B, Malyshev A, Evteev S, Terentiev V, Kamya P, Bezrukov D, Aliper A, Ren F, Zhavoronkov A. ACS Med Chem Lett 14 901-915 (2023)

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  1. FAK Inhibition disrupts a β5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth. Tancioni I, Uryu S, Sulzmaier FJ, Shah NR, Lawson C, Miller NL, Jean C, Chen XL, Ward KK, Schlaepfer DD. Mol Cancer Ther 13 2050-2061 (2014)
  2. Scope and limitations of a DMF bio-alternative within Sonogashira cross-coupling and Cacchi-type annulation. Wilson KL, Kennedy AR, Murray J, Greatrex B, Jamieson C, Watson AJ. Beilstein J Org Chem 12 2005-2011 (2016)
  3. Marine natural products-inspired phenylmethylene hydantoins with potent in vitro and in vivo antitumor activities via suppression of Brk and FAK signaling. Sallam AA, Mohyeldin MM, Foudah AI, Akl MR, Nazzal S, Meyer SA, Liu YY, El Sayed KA. Org Biomol Chem 12 5295-5303 (2014)
  4. Fragment-based discovery of focal adhesion kinase inhibitors. Grädler U, Bomke J, Musil D, Dresing V, Lehmann M, Hölzemann G, Greiner H, Esdar C, Krier M, Heinrich T. Bioorg Med Chem Lett 23 5401-5409 (2013)
  5. Steered molecular dynamics simulations for uncovering the molecular mechanisms of drug dissociation and for drug screening: A test on the focal adhesion kinase. Wong CF. J Comput Chem 39 1307-1318 (2018)
  6. Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line. Wińska P, Karatsai O, Staniszewska M, Koronkiewicz M, Chojnacki K, Rędowicz MJ. Int J Mol Sci 21 E6234 (2020)
  7. Synthesis of 2-BMIDA 6,5-bicyclic heterocycles by Cu(i)/Pd(0)/Cu(ii) cascade catalysis of 2-iodoaniline/phenols. Seath CP, Wilson KL, Campbell A, Mowat JM, Watson AJ. Chem Commun (Camb) 52 8703-8706 (2016)
  8. Qualitative Prediction of Ligand Dissociation Kinetics from Focal Adhesion Kinase Using Steered Molecular Dynamics. Spiriti J, Wong CF. Life (Basel) 11 74 (2021)
  9. Exploring the interaction between human focal adhesion kinase and inhibitors: a molecular dynamic simulation and free energy calculations. Zhan JY, Zhang JL, Wang Y, Li Y, Zhang HX, Zheng QC. J Biomol Struct Dyn 34 2351-2366 (2016)
  10. Discovery of a Pyrimidothiazolodiazepinone as a Potent and Selective Focal Adhesion Kinase (FAK) Inhibitor. Groendyke BJ, Nabet B, Mohardt ML, Zhang H, Peng K, Koide E, Coffey CR, Che J, Scott DA, Bass AJ, Gray NS. ACS Med Chem Lett 12 30-38 (2021)
  11. Drug discovery alliances in India--indications, targets, and new chemical entities. Differding E. ChemMedChem 9 43-60 (2014)
  12. Molecular Docking, Molecular Dynamics Simulations, and Free Energy Calculation Insights into the Binding Mechanism between VS-4718 and Focal Adhesion Kinase. Shi M, Chen T, Wei S, Zhao C, Zhang X, Li X, Tang X, Liu Y, Yang Z, Chen L. ACS Omega 7 32442-32456 (2022)
  13. Preparation, in vitro and in vivo evaluation, and molecular dynamics (MD) simulation studies of novel F-18 labeled tumor imaging agents targeting focal adhesion kinase (FAK). Fang Y, Wang D, Xu X, Dava G, Liu J, Li X, Xue Q, Wang H, Zhang J, Zhang H. RSC Adv 8 10333-10345 (2018)
  14. Structure-Based Discovery of a Series of 5H-Pyrrolo[2,3-b]pyrazine FGFR Kinase Inhibitors. Jiang A, Liu Q, Wang R, Wei P, Dai Y, Wang X, Xu Y, Ma Y, Ai J, Shen J, Ding J, Xiong B. Molecules 23 E698 (2018)
  15. Deprotometalation-Iodolysis and Direct Iodination of 1-Arylated 7-Azaindoles: Reactivity Studies and Molecule Properties. Ameur Messaoud MY, Bentabed-Ababsa G, Fajloun Z, Hamze M, Halauko YS, Ivashkevich OA, Matulis VE, Roisnel T, Dorcet V, Mongin F. Molecules 26 6314 (2021)


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