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Discovery of a selective kinase inhibitor (TAK-632) targeting pan-RAF inhibition: design, synthesis, and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives.

Okaniwa M, Hirose M, Arita T, Yabuki M, Nakamura A, Takagi T, Kawamoto T, Uchiyama N, Sumita A, Tsutsumi S, Tottori T, Inui Y, Sang BC, Yano J, Aertgeerts K, Yoshida S, Ishikawa T
J Med Chem 56 6478-94 (2013)
Cited: 48 times
EuropePMC logo PMID: 23906342

Abstract

With the aim of discovering a selective kinase inhibitor targeting pan-RAF kinase inhibition, we designed novel 1,3-benzothiazole derivatives based on our thiazolo[5,4-b]pyridine class RAF/VEGFR2 inhibitor 1 and developed a regioselective cyclization methodology for the C-7-substituted 1,3-benzothiazole scaffold utilizing meta-substituted anilines. Eventually, we selected 7-cyano derivative 8B (TAK-632) as a development candidate and confirmed its binding mode by cocrystal structure with BRAF. Accommodation of the 7-cyano group into the BRAF-selectivity pocket and the 3-(trifluoromethyl)phenyl acetamide moiety into the hydrophobic back pocket of BRAF in the DFG-out conformation contributed to enhanced RAF potency and selectivity vs VEGFR2. Reflecting its potent pan-RAF inhibition and slow off-rate profile, 8B demonstrated significant cellular activity against mutated BRAF or mutated NRAS cancer cell lines. Furthermore, in both A375 (BRAF(V600E)) and HMVII (NRAS(Q61K)) xenograft models in rats, 8B demonstrated regressive antitumor efficacy by twice daily, 14-day repetitive administration without significant body weight loss.

Reviews - 4ksp mentioned but not cited (1)

  1. Development of small-molecule therapeutics and strategies for targeting RAF kinase in BRAF-mutant colorectal cancer. Pan JH, Zhou H, Zhu SB, Huang JL, Zhao XX, Ding H, Pan YL. Cancer Manag Res 10 2289-2301 (2018)

Articles - 4ksp mentioned but not cited (10)

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  6. Identification of the Raf kinase inhibitor TAK-632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3. Chen X, Zhuang C, Ren Y, Zhang H, Qin X, Hu L, Fu J, Miao Z, Chai Y, Liu ZG, Zhang H, Cai Z, Wang HY. Br J Pharmacol 176 2095-2108 (2019)
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  9. research-article Allosteric coupling asymmetry mediates paradoxical activation of BRAF. Rasmussen DM, Semonis MM, Muretta JM, Thompson AR, Thomas DD, Pomerantz WCK, Levinson NM. bioRxiv 2023.04.18.536450 (2023)
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  2. New perspectives for targeting RAF kinase in human cancer. Karoulia Z, Gavathiotis E, Poulikakos PI. Nat Rev Cancer 17 676-691 (2017)
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  12. The non-linearity of RAF-MEK signaling in dendritic cells. Riegel K, Rajalingam K. Cell Cycle 19 2249-2259 (2020)
  13. From (Tool)Bench to Bedside: The Potential of Necroptosis Inhibitors. Gardner CR, Davies KA, Zhang Y, Brzozowski M, Czabotar PE, Murphy JM, Lessene G. J Med Chem 66 2361-2385 (2023)
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  3. 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)
  4. Establishment and application of a novel patient-derived KIAA1549:BRAF-driven pediatric pilocytic astrocytoma model for preclinical drug testing. Selt F, Hohloch J, Hielscher T, Sahm F, Capper D, Korshunov A, Usta D, Brabetz S, Ridinger J, Ecker J, Oehme I, Gronych J, Marquardt V, Pauck D, Bächli H, Stiles CD, von Deimling A, Remke M, Schuhmann MU, Pfister SM, Brummer T, Jones DT, Witt O, Milde T. Oncotarget 8 11460-11479 (2017)
  5. Activating KRAS, NRAS, and BRAF mutants enhance proteasome capacity and reduce endoplasmic reticulum stress in multiple myeloma. Shirazi F, Jones RJ, Singh RK, Zou J, Kuiatse I, Berkova Z, Wang H, Lee HC, Hong S, Dick L, Chattopadhyay N, Orlowski RZ. Proc Natl Acad Sci U S A 117 20004-20014 (2020)
  6. Benzothiazoles exhibit broad-spectrum antitumor activity: their potency, structure-activity and structure-metabolism relationships. Xie X, Yan Y, Zhu N, Liu G. Eur J Med Chem 76 67-78 (2014)
  7. Computational study on the unbinding pathways of B-RAF inhibitors and its implication for the difference of residence time: insight from random acceleration and steered molecular dynamics simulations. Niu Y, Li S, Pan D, Liu H, Yao X. Phys Chem Chem Phys 18 5622-5629 (2016)
  8. Reviving oncogenic addiction to MET bypassed by BRAF (G469A) mutation. Virzì AR, Gentile A, Benvenuti S, Comoglio PM. Proc Natl Acad Sci U S A 115 10058-10063 (2018)
  9. Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism. Abt ER, Rosser EW, Durst MA, Lok V, Poddar S, Le TM, Cho A, Kim W, Wei L, Song J, Capri JR, Xu S, Wu N, Slavik R, Jung ME, Damoiseaux R, Czernin J, Donahue TR, Lavie A, Radu CG. Cell Chem Biol 27 197-205.e6 (2020)
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  12. Energetics and structural characterization of the "DFG-flip" conformational transition of B-RAF kinase: a SITS molecular dynamics study. Shao Q, Xu Z, Wang J, Shi J, Zhu W. Phys Chem Chem Phys 19 1257-1267 (2017)
  13. Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy. Zhu J, Xin M, Xu C, He Y, Zhang W, Wang Z, Zhuang C. Acta Pharm Sin B 11 3193-3205 (2021)
  14. Rational design, synthesis, and biological evaluation of Pan-Raf inhibitors to overcome resistance. Wang L, Zhu G, Zhang Q, Duan C, Zhang Y, Zhang Z, Zhou Y, Lu T, Tang W. Org Biomol Chem 15 3455-3465 (2017)
  15. A modified gene trap approach for improved high-throughput cancer drug discovery. Morris SM, Mhyre AJ, Carmack SS, Myers CH, Burns C, Ye W, Ferrer M, Olson JM, Klinghoffer RA. Oncogene 37 4226-4238 (2018)
  16. BRAF signals to pro-apoptotic BIM to enhance AraC cytotoxicity induced in AML cells by Vitamin D-based differentiation agents. Wang X, Harrison JS, Studzinski GP. J Steroid Biochem Mol Biol 173 139-147 (2017)
  17. Discovery of New Quinolone-Based Diarylamides as Potent B-RAFV600E/C-RAF Kinase Inhibitors Endowed with Promising In Vitro Anticancer Activity. Kim HJ, Park JW, Seo S, Cho KH, Alanazi MM, Bang EK, Keum G, El-Damasy AK. Int J Mol Sci 24 3216 (2023)
  18. Investigations on the Anticancer Potential of Benzothiazole-Based Metallacycles. Mokesch S, Cseh K, Geisler H, Hejl M, Klose MHM, Roller A, Meier-Menches SM, Jakupec MA, Kandioller W, Keppler BK. Front Chem 8 209 (2020)
  19. Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-RafV600E/KDR Inhibitors Using Docking and 3D-QSAR Approaches. Liu HC, Tang SZ, Lu S, Ran T, Wang J, Zhang YM, Xu AY, Lu T, Chen YD. Int J Mol Sci 16 24451-24474 (2015)
  20. Design and synthesis of N-(4-aminopyridin-2-yl)amides as B-Raf(V600E) inhibitors. Li X, Shen J, Tan L, Zhang Z, Gao D, Luo J, Cheng H, Zhou X, Ma J, Ding K, Lu X. Bioorg Med Chem Lett 26 2760-2763 (2016)
  21. On the development of B-Raf inhibitors acting through innovative mechanisms. Pinzi L. F1000Res 11 237 (2022)
  22. Synthesis of 2-C-substituted benzothiazoles via a copper-promoted domino condensation/S-arylation/heterocyclization process. Xiang H, Qi J, He Q, Jiang M, Yang C, Deng L. Org Biomol Chem 12 4633-4636 (2014)


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