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Discovery of a novel class of exquisitely selective mesenchymal-epithelial transition factor (c-MET) protein kinase inhibitors and identification of the clinical candidate 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (PF-04217903) for the treatment of cancer.

Cui JJ, McTigue M, Nambu M, Tran-Dubé M, Pairish M, Shen H, Jia L, Cheng H, Hoffman J, Le P, Jalaie M, Goetz GH, Ryan K, Grodsky N, Deng YL, Parker M, Timofeevski S, Murray BW, Yamazaki S, Aguirre S, Li Q, Zou H, Christensen J
J Med Chem 55 8091-109 (2012)
Related entries: 3zxz, 3zze, 4ap7

Cited: 43 times
EuropePMC logo PMID: 22924734

Abstract

The c-MET receptor tyrosine kinase is an attractive oncology target because of its critical role in human oncogenesis and tumor progression. An oxindole hydrazide hit 6 was identified during a c-MET HTS campaign and subsequently demonstrated to have an unusual degree of selectivity against a broad array of other kinases. The cocrystal structure of the related oxindole hydrazide c-MET inhibitor 10 with a nonphosphorylated c-MET kinase domain revealed a unique binding mode associated with the exquisite selectivity profile. The chemically labile oxindole hydrazide scaffold was replaced with a chemically and metabolically stable triazolopyrazine scaffold using structure based drug design. Medicinal chemistry lead optimization produced 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (2, PF-04217903), an extremely potent and exquisitely selective c-MET inhibitor. 2 demonstrated effective tumor growth inhibition in c-MET dependent tumor models with good oral PK properties and an acceptable safety profile in preclinical studies. 2 progressed to clinical evaluation in a Phase I oncology setting.

Reviews - 4aoi mentioned but not cited (1)

  1. The azaindole framework in the design of kinase inhibitors. Mérour JY, Buron F, Plé K, Bonnet P, Routier S. Molecules 19 19935-19979 (2014)

Articles - 4aoi mentioned but not cited (3)



Reviews citing this publication (7)

  1. Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review. Karrouchi K, Radi S, Ramli Y, Taoufik J, Mabkhot YN, Al-Aizari FA, Ansar M. Molecules 23 E134 (2018)
  2. The potential roles of hepatocyte growth factor (HGF)-MET pathway inhibitors in cancer treatment. Parikh RA, Wang P, Beumer JH, Chu E, Appleman LJ. Onco Targets Ther 7 969-983 (2014)
  3. Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways. Martorana A, La Monica G, Lauria A. Molecules 25 E4279 (2020)
  4. Ockham's razor for the MET-driven invasive growth linking idiopathic pulmonary fibrosis and cancer. Stella GM, Gentile A, Balderacchi A, Meloni F, Milan M, Benvenuti S. J Transl Med 14 256 (2016)
  5. 3-Hydrazinoindolin-2-one derivatives: Chemical classification and investigation of their targets as anticancer agents. Ibrahim HS, Abou-Seri SM, Abdel-Aziz HA. Eur J Med Chem 122 366-381 (2016)
  6. Syntheses and Applications of 1,2,3-Triazole-Fused Pyrazines and Pyridazines. Hoffman GR, Schoffstall AM. Molecules 27 4681 (2022)
  7. The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies. Nitulescu GM, Stancov G, Seremet OC, Nitulescu G, Mihai DP, Duta-Bratu CG, Barbuceanu SF, Olaru OT. Molecules 28 5359 (2023)

Articles citing this publication (32)



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