3q4c › Citations

The crystal structure of BRAF in complex with an organoruthenium inhibitor reveals a mechanism for inhibition of an active form of BRAF kinase.

Xie P, Streu C, Qin J, Bregman H, Pagano N, Meggers E, Marmorstein R
Biochemistry 48 5187-98 (2009)
Cited: 46 times
EuropePMC logo PMID: 19371126

Abstract

Substitution mutations in the BRAF serine/threonine kinase are found in a variety of human cancers. Such mutations occur in approximately 70% of human malignant melanomas, and a single hyperactivating V600E mutation is found in the activation segment of the kinase domain and accounts for more than 90% of these mutations. Given this correlation, the molecular mechanism for BRAF regulation as well as oncogenic activation has attracted considerable interest, and activated forms of BRAF, such as BRAF(V600E), have become attractive targets for small molecule inhibition. Here we report on the identification and subsequent optimization of a potent BRAF inhibitor, CS292, based on an organometallic kinase inhibitor scaffold. A cocrystal structure of CS292 in complex with the BRAF kinase domain reveals that CS292 binds to the ATP binding pocket of the kinase and is an ATP competitive inhibitor. The structure of the kinase-inhibitor complex also demonstrates that CS292 binds to BRAF in an active conformation and suggests a mechanism for regulation of BRAF by phosphorylation and BRAF(V600E) oncogene-induced activation. The structure of CS292 bound to the active form of the BRAF kinase also provides a novel scaffold for the design of BRAF(V600E) oncogene selective BRAF inhibitors for therapeutic application.

Reviews - 3q4c mentioned but not cited (1)

  1. Point Mutation Specific Antibodies in B-Cell and T-Cell Lymphomas and Leukemias: Targeting IDH2, KRAS, BRAF and Other Biomarkers RHOA, IRF8, MYD88, ID3, NRAS, SF3B1 and EZH2. Singh K, Gollapudi S, Mittal S, Small C, Kumar J, Ohgami RS. Diagnostics (Basel) 11 600 (2021)

Articles - 3q4c mentioned but not cited (9)

  1. Comparing the suitability of autodock, gold and glide for the docking and predicting the possible targets of Ru(II)-based complexes as anticancer agents. Adeniyi AA, Ajibade PA. Molecules 18 3760-3778 (2013)
  2. Delineation of Polypharmacology across the Human Structural Kinome Using a Functional Site Interaction Fingerprint Approach. Zhao Z, Xie L, Xie L, Bourne PE. J. Med. Chem. 59 4326-4341 (2016)
  3. The yin-yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF. Kiel C, Benisty H, Lloréns-Rico V, Serrano L. Elife 5 e12814 (2016)
  4. Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling. Rukhlenko OS, Khorsand F, Krstic A, Rozanc J, Alexopoulos LG, Rauch N, Erickson KE, Hlavacek WS, Posner RG, Gómez-Coca S, Rosta E, Fitzgibbon C, Matallanas D, Rauch J, Kolch W, Kholodenko BN. Cell Syst 7 161-179.e14 (2018)
  5. Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allosteric Mechanism for Negative Regulation. Lange SM, Nelen MI, Cohen P, Kulathu Y. Structure 29 238-251.e4 (2021)
  6. Exploring Molecular Mechanisms of Paradoxical Activation in the BRAF Kinase Dimers: Atomistic Simulations of Conformational Dynamics and Modeling of Allosteric Communication Networks and Signaling Pathways. Tse A, Verkhivker GM. PLoS ONE 11 e0166583 (2016)
  7. Bioactive Salen-type Schiff Base Transition Metal Complexes as Possible Anticancer Agents. Damercheli M, Mahdi M, Mehravi B, Shafiee Ardestani M. Iran J Pharm Res 18 2055-2066 (2019)
  8. Inactivation of RIP3 kinase sensitizes to 15LOX/PEBP1-mediated ferroptotic death. Lamade AM, Wu L, Dar HH, Mentrup HL, Shrivastava IH, Epperly MW, St Croix CM, Tyurina YY, Anthonymuthu TS, Yang Q, Kapralov AA, Huang Z, Mao G, Amoscato AA, Hier ZE, Artyukhova MA, Shurin G, Rosenbaum JC, Gough PJ, Bertin J, VanDemark AP, Watkins SC, Mollen KP, Bahar I, Greenberger JS, Kagan VE, Whalen MJ, Bayır H. Redox Biol 50 102232 (2022)
  9. TWN-FS method: A novel fragment screening method for drug discovery. Yoon HR, Park GJ, Balupuri A, Kang NS. Comput Struct Biotechnol J 21 4683-4696 (2023)


Reviews citing this publication (6)

  1. Organometallic anticancer compounds. Gasser G, Ott I, Metzler-Nolte N. J. Med. Chem. 54 3-25 (2011)
  2. From genes to drugs: targeted strategies for melanoma. Flaherty KT, Hodi FS, Fisher DE. Nat. Rev. Cancer 12 349-361 (2012)
  3. Anticancer metallodrug research analytically painting the "omics" picture--current developments and future trends. Groessl M, Hartinger CG. Anal Bioanal Chem 405 1791-1808 (2013)
  4. Effects of BRAF mutations and BRAF inhibition on immune responses to melanoma. Ilieva KM, Correa I, Josephs DH, Karagiannis P, Egbuniwe IU, Cafferkey MJ, Spicer JF, Harries M, Nestle FO, Lacy KE, Karagiannis SN. Mol. Cancer Ther. 13 2769-2783 (2014)
  5. Somatic DNA mutation analysis in targeted therapy of solid tumours. Yu B, O'Toole SA, Trent RJ. Transl Pediatr 4 125-138 (2015)
  6. Vemurafenib in melanoma. Shaw HM, Nathan PD. Expert Rev Anticancer Ther 13 513-522 (2013)

Articles citing this publication (30)

  1. Structurally sophisticated octahedral metal complexes as highly selective protein kinase inhibitors. Feng L, Geisselbrecht Y, Blanck S, Wilbuer A, Atilla-Gokcumen GE, Filippakopoulos P, Kräling K, Celik MA, Harms K, Maksimoska J, Marmorstein R, Frenking G, Knapp S, Essen LO, Meggers E. J. Am. Chem. Soc. 133 5976-5986 (2011)
  2. Mutation D816V alters the internal structure and dynamics of c-KIT receptor cytoplasmic region: implications for dimerization and activation mechanisms. Laine E, Chauvot de Beauchêne I, Perahia D, Auclair C, Tchertanov L. PLoS Comput. Biol. 7 e1002068 (2011)
  3. Identification of a novel family of BRAF(V600E) inhibitors. Qin J, Xie P, Ventocilla C, Zhou G, Vultur A, Chen Q, Liu Q, Herlyn M, Winkler J, Marmorstein R. J. Med. Chem. 55 5220-5230 (2012)
  4. In vitro and in vivo evaluation of water-soluble iminophosphorane ruthenium(II) compounds. A potential chemotherapeutic agent for triple negative breast cancer. Frik M, Martínez A, Elie BT, Gonzalo O, Ramírez de Mingo D, Sanaú M, Sánchez-Delgado R, Sadhukha T, Prabha S, Ramos JW, Marzo I, Contel M. J. Med. Chem. 57 9995-10012 (2014)
  5. An organometallic inhibitor for the human repair enzyme 7,8-dihydro-8-oxoguanosine triphosphatase. Streib M, Kräling K, Richter K, Xie X, Steuber H, Meggers E. Angew. Chem. Int. Ed. Engl. 53 305-309 (2014)
  6. Structure of anticancer ruthenium half-sandwich complex bound to glycogen synthase kinase 3β. Atilla-Gokcumen GE, Di Costanzo L, Meggers E. J. Biol. Inorg. Chem. 16 45-50 (2011)
  7. Lung adenocarcinoma with BRAF G469L mutation refractory to vemurafenib. Gautschi O, Peters S, Zoete V, Aebersold-Keller F, Strobel K, Schwizer B, Hirschmann A, Michielin O, Diebold J. Lung Cancer 82 365-367 (2013)
  8. The x-ray structure of the adduct between NAMI-A and carbonic anhydrase provides insights into the reactivity of this metallodrug with proteins. Casini A, Temperini C, Gabbiani C, Supuran CT, Messori L. ChemMedChem 5 1989-1994 (2010)
  9. Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization. Kong X, Qin J, Li Z, Vultur A, Tong L, Feng E, Rajan G, Liu S, Lu J, Liang Z, Zheng M, Zhu W, Jiang H, Herlyn M, Liu H, Marmorstein R, Luo C. Org. Biomol. Chem. 10 7402-7417 (2012)
  10. Lys63-linked polyubiquitination of BRAF at lysine 578 is required for BRAF-mediated signaling. An L, Jia W, Yu Y, Zou N, Liang L, Zhao Y, Fan Y, Cheng J, Shi Z, Xu G, Li G, Yang J, Zhang H. Sci Rep 3 2344 (2013)
  11. Metal complexes as "protein surface mimetics". Hewitt SH, Wilson AJ. Chem. Commun. (Camb.) 52 9745-9756 (2016)
  12. High in Vitro and in Vivo Tumor-Selective Novel Ruthenium(II) Complexes with 3-(2'-Benzimidazolyl)-7-fluoro-coumarin. Qin QP, Wang ZF, Huang XL, Tan MX, Shi BB, Liang H. ACS Med Chem Lett 10 936-940 (2019)
  13. The phosphorylation specificity of B-RAF WT, B-RAF D594V, B-RAF V600E and B-RAF K601E kinases: an in silico study. Fratev F, Jónsdóttir SO. J. Mol. Graph. Model. 28 598-603 (2010)
  14. Assessing protein-ligand docking for the binding of organometallic compounds to proteins. Ortega-Carrasco E, Lledós A, Maréchal JD. J Comput Chem 35 192-198 (2014)
  15. Hydrogen bonding and anticancer properties of water-soluble chiral p-cymene Ru(II) compounds with amino-oxime ligands. Benabdelouahab Y, Muñoz-Moreno L, Frik M, de la Cueva-Alique I, El Amrani MA, Contel M, Bajo AM, Cuenca T, Royo E. Eur J Inorg Chem 2015 2295-2307 (2015)
  16. Molecular dynamics simulations and modelling of the residue interaction networks in the BRAF kinase complexes with small molecule inhibitors: probing the allosteric effects of ligand-induced kinase dimerization and paradoxical activation. Verkhivker GM. Mol Biosyst 12 3146-3165 (2016)
  17. Combining pharmacophore, docking and substructure search approaches to identify and optimize novel B-RafV600E inhibitors. Xu Z, Yan G, Wang G, Li B, Zhu J, Sun P, Zhang X, Luo C, Wang H, Zhu W. Bioorg. Med. Chem. Lett. 22 5428-5437 (2012)
  18. Development of organometallic S6K1 inhibitors. Qin J, Rajaratnam R, Feng L, Salami J, Barber-Rotenberg JS, Domsic J, Reyes-Uribe P, Liu H, Dang W, Berger SL, Villanueva J, Meggers E, Marmorstein R. J. Med. Chem. 58 305-314 (2015)
  19. Expression and purification of active receptor interacting protein 1 kinase using a baculovirus system. Maki JL, Tres Brazell J, Teng X, Cuny GD, Degterev A. Protein Expr. Purif. 89 156-161 (2013)
  20. An insight into the anticancer activities of Ru(II)-based metallocompounds using docking methods. Adeniyi AA, Ajibade PA. Molecules 18 10829-10856 (2013)
  21. Discovery of a novel pan-RAF inhibitor with potent anti-tumor activity in preclinical models of BRAFV600E mutant cancer. Hong SP, Ahn SK. Life Sci. 183 37-44 (2017)
  22. Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-RafV600E inhibitors. Wang GM, Wang X, Zhu JM, Guo BB, Yang Z, Xu ZJ, Li B, Wang HY, Meng LH, Zhu WL, Ding J. Acta Pharmacol. Sin. 38 1059-1068 (2017)
  23. In silico identification of novel kinase inhibitors by targeting B-Raf(v660e) from natural products database. Wang ZJ, Wan ZN, Chen XD, Wu CF, Gao GL, Liu R, Shi Z, Bao JK. J Mol Model 21 102 (2015)
  24. Editorial Targeted treatment for melanoma. Monga M, Abraham J. Expert Rev Anticancer Ther 12 1113-1115 (2012)
  25. The Anticancer Activities of Some Nitrogen Donor Ligands Containing bis-Pyrazole, Bipyridine, and Phenanthroline Moiety Using Docking Methods. Adeniyi AA, Ajibade PA. Bioinorg Chem Appl 2018 5796287 (2018)
  26. BRAFnon-V600E more frequently co-occurs with IDH1/2 mutations in adult patients with gliomas than in patients harboring BRAFV600E but without a survival advantage. Wang W, Wang M, Jiang H, Wang T, Da R. BMC Neurol 21 195 (2021)
  27. Development of the first model of a phosphorylated, ATP/Mg2+-containing B-Raf monomer by molecular dynamics simulations: a tool for structure-based design. Previtali V, Trujillo C, Boisson JC, Khartabil H, Hénon E, Rozas I. Phys Chem Chem Phys 19 31177-31185 (2017)
  28. Integrating docking scores and key interaction profiles to improve the accuracy of molecular docking: towards novel B-RafV600E inhibitors. Hu CQ, Li K, Yao TT, Hu YZ, Ying HZ, Dong XW. Medchemcomm 8 1835-1844 (2017)
  29. Mechanism of BRAF Activation through Biochemical Characterization of the Recombinant Full-Length Protein. Cope N, Candelora C, Wong K, Kumar S, Nan H, Grasso M, Novak B, Li Y, Marmorstein R, Wang Z. Chembiochem 19 1988-1997 (2018)
  30. Synthesis, structural characterization, QSAR and docking studies of a new binuclear nickel (II) complex based on the flexible tetradentate N-donor ligand as a potent antibacterial and anticancer agent. Beheshti A, Hashemi F, Behavndi F, Zahedi M, Kolahi M, Motamedi H, Mayer P. Int. J. Biol. Macromol. 104 1107-1123 (2017)


Quick links