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Tyrosine kinase inhibitor

December 20, 2023

A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia. They have also been used to treat other diseases, such as idiopathic pulmonary fibrosis.

Crystal structure of the second generation Bcr-Abl tyrosine-kinase inhibitor nilotinib (red) in complex with an Abl kinase domain (blue). Nilotinib is used to treat chronic myelogenous leukemia (CML), a hematological malignancy.

They are also called tyrphostins, the short name for "tyrosine phosphorylation inhibitor", originally coined in a 1988 publication,[1] which was the first description of compounds inhibiting the catalytic activity of the epidermal growth factor receptor (EGFR).

The 1988 study was the first demonstration of a systematic search and discovery of small-molecular-weight inhibitors of tyrosine phosphorylation, which do not inhibit protein kinases that phosphorylate serine or threonine residues and can discriminate between the kinase domains of the EGFR and that of the insulin receptor. It was further shown that in spite of the conservation of the tyrosine-kinase domains one can design and synthesize tyrphostins that discriminate between even closely related protein tyrosine kinases such as EGFR and its close relative HER2.[2][3]

Development of drugs edit

Numerous TKIs aiming at various tyrosine kinases have been generated by the originators of these compounds and proven to be effective anti-tumor agents and anti-leukemic agents.[4][5] Based on this work imatinib was developed against chronic myelogenous leukemia (CML)[6] and later gefitinib and erlotinib aiming at the EGF receptor. Dasatinib is a Src tyrosine kinase inhibitor that is effective both as a senolytic and as therapy for CML.[7]

Sunitinib, an inhibitor of the receptors for FGF, PDGF and VEGF is also based on early studies on TKIs aiming at VEGF receptors.[8]

Adavosertib is a Wee1 kinase inhibitor that is undergoing numerous clinical trials in the treatment of refractory solid tumors.[9] However, toxicities such as myelosuppression, diarrhea, and supraventricular tachyarrhythmia have arisen while attempting to determine the toxicity and effectiveness of the drug.[10]

Lapatinib, FDA approved for treatment in conjunction with chemotherapy or hormone therapy, is also currently undergoing clinical trials in the treatment of HER2-overexpressing breast cancers as it is suggested intermittent high-dose therapy might have better efficacy with manageable toxicity than the standard continuous dosing. A Phase I clinical trial found responses and dramatic responses to this line of treatment, with the most common toxicity being diarrhea.[11]

Mechanisms edit

TKIs operate by four different mechanisms: they can compete with adenosine triphosphate (ATP), the phosphorylating entity, the substrate or both or can act in an allosteric fashion, namely bind to a site outside the active site, affecting its activity by a conformational change.[12] Recently TKIs have been shown to deprive tyrosine kinases of access to the Cdc37-Hsp90 molecular chaperone system on which they depend for their cellular stability, leading to their ubiquitylation and degradation.[13] Signal transduction therapy can also be used for non-cancer proliferative diseases and for inflammatory conditions.[14] An example is nintedanib for the treatment of idiopathic pulmonary fibrosis.[15]

See also edit

References edit

  1. ^ Yaish P, Gazit A, Gilon C, Levitzki A (1988). "Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors". Science. 242 (4880): 933–935. Bibcode:1988Sci...242..933Y. doi:10.1126/science.3263702. PMID 3263702. S2CID 9593087.
  2. ^ Gazit A, Osherov N, Posner I, Yaish P, Poradosu E, Gilon C, Levitzki A (1991). "Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases". J Med Chem. 34 (6): 1896–907. doi:10.1021/jm00110a022. PMID 1676428.
  3. ^ Osherov N, Gazit A, Gilon C, Levitzki A (1993). "Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins". J Biol Chem. 268 (15): 11134–42. doi:10.1016/S0021-9258(18)82102-0. PMID 8098709.
  4. ^ Anafi M, Gazit A, Zehavi A, Ben-Neriah Y, Levitzki A (1993). "Tyrphostin-induced inhibition of p210bcr-abl tyrosine kinase activity induces K562 to differentiate". Blood. 82 (12): 3524–9. doi:10.1182/blood.V82.12.3524.3524. PMID 7505115.
  5. ^ Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifman CM (1996). "Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor". Nature. 379 (6566): 645–8. Bibcode:1996Natur.379..645M. doi:10.1038/379645a0. PMID 8628398. S2CID 2528506.
  6. ^ Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996). "Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells". Nat Med. 2 (5): 561–6. doi:10.1038/nm0596-561. PMID 8616716. S2CID 36102747.
  7. ^ Rivera-Torres J, José ES (2019). "Src Tyrosine Kinase Inhibitors: New Perspectives on Their Immune, Antiviral, and Senotherapeutic Potential". Frontiers in Pharmacology. 10: 1011. doi:10.3389/fphar.2019.01011. PMC 6759511. PMID 31619990.
  8. ^ Strawn LM, McMahon G, App H, Schreck R, Kuchler WR, Longhi MP, Hui TH, Tang C, Levitzki A, Gazit A, Chen I, Keri G, Orfi L, Risau W, Flamme I, Ullrich A, Hirth KP, Shawver LK (1996). "Flk-1 as a target for tumor growth inhibition". Cancer Res. 56 (15): 3540–5. PMID 8758924.
  9. ^ "NCI drug dictionary adavosertib". National Cancer Dictionary. 2 February 2011. Retrieved April 20, 2018.
  10. ^ Do K, et al. (October 2015). "Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors". Journal of Clinical Oncology. 33 (30): 3409–15. doi:10.1200/JCO.2014.60.4009. PMC 4606059. PMID 25964244.
  11. ^ Chien AJ, et al. (May 2014). "Phase I dose-escalation study of 5-day intermittent oral lapatinib therapy in patients with human epidermal growth factor receptor 2–overexpressing breast cancer". Journal of Clinical Oncology. 32 (14): 1472–79. doi:10.1200/JCO.2013.52.1161. PMC 4017711. PMID 24711549.
  12. ^ Posner I, Engel M, Gazit A, Levitzki A (1994). "Kinetics of inhibition by tyrphostins of the tyrosine kinase activity of the epidermal growth factor receptor and analysis by a new computer program". Mol. Pharmacol. 45 (4): 673–83. PMID 8183246.
  13. ^ Polier; et al. (2013). "ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system". Nature Chemical Biology. 9 (5): 307–312. doi:10.1038/nchembio.1212. PMC 5695660. PMID 23502424.
  14. ^ Levitzki A, Mishani E (2006). "Tyrphostins and other tyrosine kinase inhibitors". Annu Rev Biochem. 75: 93–109. doi:10.1146/annurev.biochem.75.103004.142657. PMID 16756486.
  15. ^ "Vargatef EPAR". European Medicines Agency (EMA). 20 January 2020.

December 20, 2023
tyrosine, kinase, inhibitor, tyrosine, kinase, inhibitor, pharmaceutical, drug, that, inhibits, tyrosine, kinases, tyrosine, kinases, enzymes, responsible, activation, many, proteins, signal, transduction, cascades, proteins, activated, adding, phosphate, grou. A tyrosine kinase inhibitor TKI is a pharmaceutical drug that inhibits tyrosine kinases Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades The proteins are activated by adding a phosphate group to the protein phosphorylation a step that TKIs inhibit TKIs are typically used as anticancer drugs For example they have substantially improved outcomes in chronic myelogenous leukemia They have also been used to treat other diseases such as idiopathic pulmonary fibrosis Crystal structure of the second generation Bcr Abl tyrosine kinase inhibitor nilotinib red in complex with an Abl kinase domain blue Nilotinib is used to treat chronic myelogenous leukemia CML a hematological malignancy They are also called tyrphostins the short name for tyrosine phosphorylation inhibitor originally coined in a 1988 publication 1 which was the first description of compounds inhibiting the catalytic activity of the epidermal growth factor receptor EGFR The 1988 study was the first demonstration of a systematic search and discovery of small molecular weight inhibitors of tyrosine phosphorylation which do not inhibit protein kinases that phosphorylate serine or threonine residues and can discriminate between the kinase domains of the EGFR and that of the insulin receptor It was further shown that in spite of the conservation of the tyrosine kinase domains one can design and synthesize tyrphostins that discriminate between even closely related protein tyrosine kinases such as EGFR and its close relative HER2 2 3 Contents 1 Development of drugs 2 Mechanisms 3 See also 4 ReferencesDevelopment of drugs editNumerous TKIs aiming at various tyrosine kinases have been generated by the originators of these compounds and proven to be effective anti tumor agents and anti leukemic agents 4 5 Based on this work imatinib was developed against chronic myelogenous leukemia CML 6 and later gefitinib and erlotinib aiming at the EGF receptor Dasatinib is a Src tyrosine kinase inhibitor that is effective both as a senolytic and as therapy for CML 7 Sunitinib an inhibitor of the receptors for FGF PDGF and VEGF is also based on early studies on TKIs aiming at VEGF receptors 8 Adavosertib is a Wee1 kinase inhibitor that is undergoing numerous clinical trials in the treatment of refractory solid tumors 9 However toxicities such as myelosuppression diarrhea and supraventricular tachyarrhythmia have arisen while attempting to determine the toxicity and effectiveness of the drug 10 Lapatinib FDA approved for treatment in conjunction with chemotherapy or hormone therapy is also currently undergoing clinical trials in the treatment of HER2 overexpressing breast cancers as it is suggested intermittent high dose therapy might have better efficacy with manageable toxicity than the standard continuous dosing A Phase I clinical trial found responses and dramatic responses to this line of treatment with the most common toxicity being diarrhea 11 Mechanisms editTKIs operate by four different mechanisms they can compete with adenosine triphosphate ATP the phosphorylating entity the substrate or both or can act in an allosteric fashion namely bind to a site outside the active site affecting its activity by a conformational change 12 Recently TKIs have been shown to deprive tyrosine kinases of access to the Cdc37 Hsp90 molecular chaperone system on which they depend for their cellular stability leading to their ubiquitylation and degradation 13 Signal transduction therapy can also be used for non cancer proliferative diseases and for inflammatory conditions 14 An example is nintedanib for the treatment of idiopathic pulmonary fibrosis 15 See also editBcr Abl tyrosine kinase inhibitor Protein kinase inhibitorReferences edit Yaish P Gazit A Gilon C Levitzki A 1988 Blocking of EGF dependent cell proliferation by EGF receptor kinase inhibitors Science 242 4880 933 935 Bibcode 1988Sci 242 933Y doi 10 1126 science 3263702 PMID 3263702 S2CID 9593087 Gazit A Osherov N Posner I Yaish P Poradosu E Gilon C Levitzki A 1991 Tyrphostins 2 Heterocyclic and alpha substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2 neu tyrosine kinases J Med Chem 34 6 1896 907 doi 10 1021 jm00110a022 PMID 1676428 Osherov N Gazit A Gilon C Levitzki A 1993 Selective inhibition of the epidermal growth factor and HER2 neu receptors by tyrphostins J Biol Chem 268 15 11134 42 doi 10 1016 S0021 9258 18 82102 0 PMID 8098709 Anafi M Gazit A Zehavi A Ben Neriah Y Levitzki A 1993 Tyrphostin induced inhibition of p210bcr abl tyrosine kinase activity induces K562 to differentiate Blood 82 12 3524 9 doi 10 1182 blood V82 12 3524 3524 PMID 7505115 Meydan N Grunberger T Dadi H Shahar M Arpaia E Lapidot Z Leeder JS Freedman M Cohen A Gazit A Levitzki A Roifman CM 1996 Inhibition of acute lymphoblastic leukaemia by a Jak 2 inhibitor Nature 379 6566 645 8 Bibcode 1996Natur 379 645M doi 10 1038 379645a0 PMID 8628398 S2CID 2528506 Druker BJ Tamura S Buchdunger E Ohno S Segal GM Fanning S Zimmermann J Lydon NB 1996 Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr Abl positive cells Nat Med 2 5 561 6 doi 10 1038 nm0596 561 PMID 8616716 S2CID 36102747 Rivera Torres J Jose ES 2019 Src Tyrosine Kinase Inhibitors New Perspectives on Their Immune Antiviral and Senotherapeutic Potential Frontiers in Pharmacology 10 1011 doi 10 3389 fphar 2019 01011 PMC 6759511 PMID 31619990 Strawn LM McMahon G App H Schreck R Kuchler WR Longhi MP Hui TH Tang C Levitzki A Gazit A Chen I Keri G Orfi L Risau W Flamme I Ullrich A Hirth KP Shawver LK 1996 Flk 1 as a target for tumor growth inhibition Cancer Res 56 15 3540 5 PMID 8758924 NCI drug dictionary adavosertib National Cancer Dictionary 2 February 2011 Retrieved April 20 2018 Do K et al October 2015 Phase I study of single agent AZD1775 MK 1775 a Wee1 kinase inhibitor in patients with refractory solid tumors Journal of Clinical Oncology 33 30 3409 15 doi 10 1200 JCO 2014 60 4009 PMC 4606059 PMID 25964244 Chien AJ et al May 2014 Phase I dose escalation study of 5 day intermittent oral lapatinib therapy in patients with human epidermal growth factor receptor 2 overexpressing breast cancer Journal of Clinical Oncology 32 14 1472 79 doi 10 1200 JCO 2013 52 1161 PMC 4017711 PMID 24711549 Posner I Engel M Gazit A Levitzki A 1994 Kinetics of inhibition by tyrphostins of the tyrosine kinase activity of the epidermal growth factor receptor and analysis by a new computer program Mol Pharmacol 45 4 673 83 PMID 8183246 Polier et al 2013 ATP competitive inhibitors block protein kinase recruitment to the Hsp90 Cdc37 system Nature Chemical Biology 9 5 307 312 doi 10 1038 nchembio 1212 PMC 5695660 PMID 23502424 Levitzki A Mishani E 2006 Tyrphostins and other tyrosine kinase inhibitors Annu Rev Biochem 75 93 109 doi 10 1146 annurev biochem 75 103004 142657 PMID 16756486 Vargatef EPAR European Medicines Agency EMA 20 January 2020 Retrieved from https en wikipedia org w index php title Tyrosine kinase inhibitor amp oldid 1093366672, wikipedia, wiki, book, books, library,

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