MAP kinase inhibitor

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A MAP kinase inhibitor is an inhibitor of the MAP kinase pathway and, as a tyrosine kinase inhibitor or serine / threonine kinase inhibitor, belongs to the protein kinase inhibitors .

properties

MAP kinases ( mitogen- activated protein kinases) are tyrosine kinases that are involved in the regulation of various cellular processes, e.g. B. Cell division and differentiation . Some oncogenes are MAP kinases, which is why inhibitors are used to treat tumors , e.g. B. BRAF inhibitors in BRAF-mutated melanoma or K-Ras inhibitors in colon cancer .

Raf inhibitors are z. B. SB590885, PLX4720, XL281, RAF265, encorafenib , dabrafenib and vemurafenib .

Various MEK inhibitors have been developed, including trametinib (GSK1120212, partly with Dabrafenib) Selumetinib , Binimetinib or MEK162 , PD-325901 , Cobimetinib or XL518 (in combination with vemurafenib), U0126 , CI-1040 , and PD035901 .

JN kinases (JNK) are involved in type II diabetes mellitus , rheumatism and neuronal excitotoxicity after ischemia . JNK inhibitors are being investigated for the treatment of inflammatory processes. The JNK inhibitor AM-111 is used to treat some forms of hearing loss.

Most previous inhibitors of p38 are too hepatotoxic for use in humans.

Individual evidence

  1. ↑ Ding Wang, Scott A. Boerner, James D. Winkler, Patricia M. Lorusso: Clinical experience of MEK inhibitors in cancer therapy . In: Biochim Biophys Acta . 1773, No. 8, 2007, pp. 1248-55. doi : 10.1016 / j.bbamcr.2006.11.009 . PMID 17194493 .
  2. ↑ Kim DH, Sim T: Novel small molecule Raf kinase inhibitors for targeted cancer therapeutics . In: Arch Pharm Res . 35, No. 4, March 2012, pp. 605-15. doi : 10.1007 / s12272-012-0403-5 . PMID 22553052 .
  3. ↑ Matsuda Y, Fukumoto M: Sorafenib: complexities of Raf-dependent and Raf-independent signaling are now unveiled . In: Med Mol Morphol . 44, No. 4, December 2011, pp. 183-9. doi : 10.1007 / s00795-011-0558-z . PMID 22179180 .
  4. ↑ Pasi A Jänne, Alice T Shaw, José Rodrigues Pereira, Gaëlle Jeannin, Johan Vansteenkiste, Carlos Barrios, Fabio Andre Franke, Lynda Grinsted et al: Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: A randomized, multicentre, placebo-controlled, phase 2 study . In: The Lancet Oncology . 14, No. 1, 2013, pp. 38-47. doi : 10.1016 / S1470-2045 (12) 70489-8 . PMID 23200175 .
  5. ↑ Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS: A central role for JNK in obesity and insulin resistance . In: Nature . 420, No. 6913, November 2002, pp. 333-6. doi : 10.1038 / nature01137 . PMID 12447443 .
  6. ↑ SE Sweeney, GS Firestein: Mitogen activated protein kinase inhibitors: where are we now and where are we going? In: Annals of the Rheumatic Diseases . Volume 65 Suppl 3, November 2006, ISSN  0003-4967 , pp. Iii83-iii88, doi : 10.1136 / ard.2006.058388 , PMID 17038480 , PMC 1798373 (free full text).
  7. ↑ Bogoyevitch MA, Boehm I, Oakley A, Ketterman AJ, Barr RK: Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential . In: Biochim. Biophys. Acta . 1697, No. 1-2, March 2004, pp. 89-101. doi : 10.1016 / j.bbapap.2003.11.016 . PMID 15023353 .
  8. ↑ RP Gangwal, A. Bhadauriya, MV Damre, GV Dhoke, AT Sangamwar: p38 Mitogen -activated protein kinase inhibitors: a review on pharmacophore mapping and QSAR studies. In: Current Topics in Medicinal Chemistry . Volume 13, Number 9, 2013, ISSN  1873-4294 , pp. 1015-1035, PMID 23651481 .
  9. ↑ Wang J, Van De Water TR, Bonny C, de Ribaupierre F, Puel JL, Zine A: A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss . In: J. Neurosci. . 23, No. 24, September 2003, pp. 8596-607. PMID 13679429 .
  10. ↑ Genovese MC: Inhibition of p38: has the fat lady sung? . In: Arthritis Rheum . 60, No. 2, February 2009, pp. 317-20. doi : 10.1002 / art.24264 . PMID 19180514 .
  11. ↑ S. Bühler, SA Laufer: p38 MAPK inhibitors: a patent review (2012-2013). In: Expert Opinion on Therapeutic Patents . Volume 24, number 5, May 2014, ISSN  1744-7674 , pp. 535-554, doi : 10.1517 / 13543776.2014.894977 , PMID 24611721 .