A novel RAF kinase inhibitor with DFG-out-binding mode: High efficacy in BRAF-mutant tumor xenograft models in the absence of normal tissue hyperproliferation

Molecular Cancer Therapeutics

Volumn 15, Issue 3, 2016, Pages 354-365

  Waizenegger, Irene C ^a   Baum, Anke ^a   Steurer, Steffen ^a   Stadtmüller, Heinz ^a   Bader, Gerd ^a   Schaaf, Otmar ^a   Garin Chesa, Pilar ^a   Schlattl, Andreas ^a   Schweifer, Norbert ^a   Haslinger, Christian ^a   Colbatzky, Florian ^b   Mousa, Sien ^b,c   Kalkuhl, Arno ^b   Kraut, Norbert ^a   Adolf, Günther R ^a  

^a BOEHRINGER INGELHEIM RCV GMBH AND CO KG   (Austria)

^b BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

^c Janssen Pharmaceutica NV   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

2 [4 (1 HYDROXYIMINO 5 INDANYL) 3 (4 PYRIDINYL) 1H PYRAZOL 1 YL]ETHANOL; AFATINIB; ANTINEOPLASTIC AGENT; B RAF KINASE; B RAF KINASE INHIBITOR; BI 882370; CETUXIMAB; DABRAFENIB; IRINOTECAN; TRAMETINIB; UNCLASSIFIED DRUG; VEMURAFENIB; BIOLOGICAL MARKER; ISOENZYME; PROTEIN KINASE INHIBITOR;

A375 CELL LINE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; BLOOD SAMPLING; CANCER GROWTH; CANCER REGRESSION; CANCER RESISTANCE; CELL COUNT; CELL CULTURE; COLORECTAL CARCINOMA; CONTROLLED STUDY; DIMERIZATION; DOSE RESPONSE; DRUG BINDING SITE; DRUG EFFICACY; DRUG POTENCY; DRUG SAFETY; DRUG TOLERABILITY; EC50; FEASIBILITY STUDY; FEMALE; HUMAN; HUMAN CELL; IC50; IMMUNOBLOTTING; IMMUNOHISTOCHEMISTRY; MELANOMA; MELANOMA CELL; MOUSE; NONHUMAN; PRIORITY JOURNAL; RAT; SCANNING ELECTRON MICROSCOPY; TUMOR REGRESSION; TUMOR XENOGRAFT; WEIGHT REDUCTION; X RAY CRYSTALLOGRAPHY; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL PROLIFERATION; CHEMICAL STRUCTURE; CHEMISTRY; CONFORMATION; DISEASE MODEL; DRUG EFFECTS; DRUG RESISTANCE; DRUG SCREENING; ENZYME ACTIVATION; GENETICS; MALE; METABOLISM; MOLECULAR MODEL; MUTATION; NEOPLASMS; PATHOLOGY; PROTEIN MULTIMERIZATION; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC AGENTS; BIOMARKERS; CELL LINE, TUMOR; CELL PROLIFERATION; DISEASE MODELS, ANIMAL; DRUG RESISTANCE, NEOPLASM; ENZYME ACTIVATION; FEMALE; HUMANS; ISOENZYMES; MALE; MICE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; MUTATION; NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTEIN MULTIMERIZATION; PROTO-ONCOGENE PROTEINS B-RAF; RATS; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84964318616     PISSN: 15357163     EISSN: 15388514     Source Type: Journal    
DOI: 10.1158/1535-7163.MCT-15-0617     Document Type: Article

References (42)

1. Wimmer R, Baccarini M. Partner exchange: protein-protein interactions in the Raf pathway. Trends Biochem Sci 2010;35:660-8.
2. Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov 2014;13:928-42.
3. Welsh SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol 2015;7:122-36.
4. Gibney GT, Messina JL, Fedorenko IV, Sondak VK, Smalley KS. Paradoxical oncogenesis-the long-term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol 2013;10:390-9.
5. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015;372:30-9.
6. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, De Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015;386:444-51.
7. Girotti MR, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, et al. Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma. Cancer Cell 2015;27:85-96.
8. Torti VR, Wojciechowicz D, Hu W, John-Baptiste A, Evering W, Troche G, et al. Epithelial tissue hyperplasia induced by the RAF inhibitor PF-04880594 is attenuated by a clinically well-tolerated dose of the MEK inhibitor PD-0325901. Mol Cancer Ther 2012;11:2274-83.
9. Wisler JA, Afshari C, Fielden M, Zimmermann C, Taylor S, Carnahan J, et al. Raf inhibition causes extensive multiple tissue hyperplasia and urinary bladder neoplasia in the rat. Toxicol Pathol 2011;39:809-22.
10. King AJ, Arnone MR, Bleam MR, Moss KG, Yang J, Fedorowicz KE, et al. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One 2013;8:e67583.
11. Stadtmueller H, inventor; Boehringer Ingelheim International GmbH, assignee. New azyindolylphenyl sulfonamides as serine/threonine kinase inhibitors). WO2012/104388 A1. 2012.
12. Himmelsbach F, Langkopf E, Blech S, Jung B, Baum ESF, inventors; Boehringer Ingelheim Pharma KG, assignee. Quinazoline derivatives, medicaments containing said compounds, their utilization and method for the production thereof. WO2002/50043 A1. 2002.
13. Ibrahim PN, Artis DR, Bremer R, Mamo S, Nespi M, Zhang C, et al., inventors; Plexxikon, Inc., assignee. Pyrrolo (2, 3-B) pyridine derivatives as protein kinase inhibitors. WO2007/002325 A1. 2007.
14. Desai D, Diodone R, Go Z, Ibrahim PN, Iyer RM, Mair H-J, et al., inventors; F. Hoffmann-La Roche AG; Plexxikon, Inc, assignees. Compositions and uses thereof. WO2010/114928 A2. 2010.
15. Adams JL, Dickerson SH, Johnson NW, Kuntz K, Petrov K, Ralph JM, et al., inventors; Smithkline Beecham Coorporation, assignee. Benzene sulfonamide thiazole and oxazole compounds. WO2009/137391 A2. 2009.
16. Sakai T, Kawasaki H, Abe H, Hayakawa K, Iida T, Kikuchi S, et al., inventors; Japan Tobacco INC., assignee. 5-Amino-2, 4, 7-Trioxo-2, 4, 7, 8-Tetrahydro-2H-Pyrido-2, 3D-Pyrimidine derivate and related compounds for the treatment of cancer. WO2005/121142 A1. 2005.
17. Laird E, Lyssikatos JP, Welch M, Grina J, Hansen J, Newhouse B, et al., inventors; Genentech, INC.; Array Biopharma, Inc., assignees. Raf inhibitor compounds and methods. WO2006/084015 A2. 2006.
18. Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A 2008;105:3041-6.
19. Kabsch W. XDS. Biol Crystallogr Online 2010;66:125-32.
20. Emsley P, Lohkamp B, Scott WG, Cowtan K. Features and development of Coot. Acta Crystallogr D Biol Crystallogr 2010;66:486-501.
21. Murshudov GN, Vagin AA, Dodson EJ. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr 1997;53:240-55.
22. Neumann L, Von KK, Ullmann D. HTS reporter displacement assay for fragment screening and fragment evolution toward leads with optimized binding kinetics, binding selectivity, and thermodynamic signature. Methods Enzymol 2011;493:299-320.
23. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010;140:209-21.
24. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010;464:427-30.
25. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010;464:431-5.
26. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809-19.
27. Wang J, Earp J, Grimstein C, Mehrotra N, Orbach RC, Pacanowski M, et al. Clinical pharmacology and biopharmaceutics review 202806/S-000 Part 01; 2013. Available from: https://www.pharmapendium.com/fda.do? query=%28202806Orig1s000%29&includeSynonyms=true&drugName-=Dabrafenib+Mesylate&document=b85ba5032af11ea8797fd933e8495-6e8.
28. Leong R, Yu J, Shord S, Mehrotra N, Orbach RC, Pacanowski M, et al. Clinical pharmcology and biopharmaceutics review 204114/S-000 part 01; 2013. Available from: https://www.pharmapendium.com/fda.do? query=%28204114Orig1s000%29&includeSynonyms=true&drug-Name=Trametinib+Dimethyl+Sulfoxide&document=036279dde5f64-e7c0505e441d38a0646.
29. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010;468:968-72.
30. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF (V600E) inhibition by RTK or N-RAS upregulation. Nature 2010;468:973-7.
31. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 2010;18:683-95.
32. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, et al. Dissecting therapeutic resistance to RAF inhibition inmelanoma by tumor genomic profiling. J Clin Oncol 2011;29:3085-96.
33. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF (V600E). Nature 2011;480:387-90.
34. Yang H, Higgins B, Kolinsky K, Packman K, Bradley WD, Lee RJ, et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res 2012;72:779-89.
35. Prahallad A, Sun C, Huang S, Di NF, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF (V600E) inhibition through feedback activation of EGFR. Nature 2012;483:100-3.
36. Obenauf AC, Zou Y, Ji AL, Vanharanta S, Shu W, Shi H, et al. Therapyinduced tumour secretomes promote resistance and tumour progression. Nature 2015;520:368-72.
37. Hirata E, Girotti MR, Viros A, Hooper S, Spencer-Dene B, Matsuda M, et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin beta1/FAK signaling. Cancer Cell 2015;27:574-88.
38. Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2006;2:358-64.
39. Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 2015;162:1271-85.
40. Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, et al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol 2013;31:482-9.
41. Coffee EM, Faber AC, Roper J, Sinnamon MJ, Goel G, Keung L, et al. Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF (V600E) colorectal cancer. Clin Cancer Res 2013;19:2688-98.
42. Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, et al. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature 2015;526:583-6.