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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Protein Kinase Inhibitors

Last Update: April 12, 2019.

OVERVIEW

The kinase inhibitors are a large group of unique and potent antineoplastic agents which specifically target protein kinases that are altered in cancer cells and that account for some of their abnormal growth. Protein kinases are ubiquitous intracellular and cell surface proteins that play critical roles in cell signaling pathways involved in metabolism, injury responses, adaption, growth and differentiation. They act by adding a phosphate group to a protein (phosphorylation), usually on a specific amino acid which often makes the protein or enzyme "active". The human genome has more than 500 protein kinases and they can be classified as (1) tyrosine, (2) serine-theonine or (3) nonspecific (both), based upon their amino acid specificity. Many protein kinases are cell surface receptors and act to initiate an intracellular pathway of activation, after the receptor is engaged by its ligand, typically a cytokine or growth factor. Inhibitors of these kinases are called protein kinase receptor inhibitors. Other kinases are intracellular and take part in cell signaling. These kinases can be targeted by "non-receptor" protein kinases. Finally, some kinase inhibitors have specificity for multiple kinases and are called "multi-kinase inhibitors."

Protein kinases can be specifically involved in cell growth, proliferation and differentiation and mutations may lead to unregulated growth and proliferation that is typical of cancerous cells. These mutated protein kinases represent an attractive target for anticancer agents. The potent activity and lack of generalized toxicity of the kinase inhibitors relate to the specificity of antagonist for the mutated protein. In like manner, their toxicity often relates to off-target activity, either to the unmutated kinase or to closely related, normal kinases.

The protein kinases can be categorized based upon the amino acid that they phosphorylate: either serine, threonine or tyrosine. The tyrosine kinase receptor inhibitors were the initial and are perhaps the best characterized kinase inhibitors. The protein kinase inhibitors are relatively recently developed agents, all having been introduced since 2001. They are unique and represent a major advance in cancer chemotherapy, away from broadly cytotoxic agents and towards drugs that specifically target the molecular abnormalities of cancer cells. The initial tyrosine kinase inhibitor approved for use in the United States was imatinib (Gleevec: 2001) which is used to treat Philadelphia chromosome positive chronic lymphocytic leukemia, which has a mutated kinase receptor (BCR-ABL) that is created by the specific translocation that creates the Philadelphia chromosome. Imatinib is a specific inhibitor of the BCR-ABL kinase. The introduction of this first protein kinase inhibitor was followed by more than a dozen others within the next 10 years.

While most kinase inhibitors are antineoplastic agents, a few are also used for benign conditions including macular degeneration (pegaptanib), rheumatoid arthritis (tofacitinib) and idiopathic pulmonary fibrosis (nintedanib). Generally, however, the side effect profile of kinase inhibitors are such that they are reserved for severe, progressive, debilitating or potentially fatal conditions.

The protein kinase inhibitors all have some degree of hepatotoxicity and many have been linked to cases of clinically apparent liver injury which can be severe and even fatal. Interestingly, some of the cases of liver injury attributed to the protein kinase antagonists had features of autoimmunity, so that the liver injury may be caused by an immunologic reaction to metabolic products of the agent itself, rather than off-target activity of the inhibitor. In addition, at least two protein kinase inhibitors (imatinib and nilotinib) have been linked to instances of reactivation of hepatitis B. It is not clear whether this relates to a specific activity of the kinase inhibitor on hepatitis B virus replication or whether it is due to immunosuppression. Other kinase inhibitors have been linked to cases of rare and idiosyncratic liver injury, which can be hepatocellular or cholestatic and is typically self-limited but may be fatal.

The Table below lists the protein kinase inhibitors discussed in LiverTox, their brand name, predominant protein kinase (PK) specificity, year of approval in the United States, likelihood score, and major clinical uses.

PROTEIN KINASE INHIBITORS

Underlined Generic Names link to a LiverTox record.

CANCER
Generic Name Brand Name Kinase
Target
ApprovalLikelihood
Score
Major Uses
Abemaciclib
Verzenio
Cyclin dependent kinase 4/62017E*Breast cancer
Acalabrutinib CalquenceBruton kinase2017DMantel cell lymphoma
Afatinib
Gilotrif
EGFR, HER22013DNSCLC
Alectinib
Alecensa
ALK2015DNSCLC
Axitinib
Inlyta
VEGFR 1-32012ERenal cell cancer
Binimetinib
Mektovi
BRAF2018E*Melanoma
Bortezomib
Velcade
Proteasome2003CMultiple myeloma, Mantle cell lymphoma
Bosutinib
Bosulif
BCR-ABL, scr2012E*CML, resistant
Brigatinib
Alunbrig
ALK2017E*NSCLC
Cabozantinib Cometriq, CabometyxMET, VEGFR-22012E*Medullary thyroid cancer, Renal cell cancer
Carfilzomib
Kyprolis
Proteasome2012E*Multiple myeloma, resistant
Ceritinib
Zykadia
ALK2014DNSCLC
Cobimetinib
Cotellic
MEK2015DMelanoma
Copanlisib
Aliqopa
PI3Kα/δ2017E*Follicular lymphoma
Crizotinib
Xalkori
ALK2011DNSCLC
Dabrafenib
Tafinlar
BRAF2013E*Melanoma
Dacomitinib
Vizimpro
HER1,2,32018E*NSCLC
Dasatinib
Sprycel
BCR-ABL, src2006DCML, resistant
Duvelisib
Copiktra
PI3K2018E*CLL, Small cell lymphoma
Enasidenib
IDHIFA
Mutant IDH-22017E*AML
Encorafenib
Braftovi
BRAF2018E*Melanoma
Erlotinib
Tarceva
EGFR, HER12004CNSCLC, Pancreatic cancer
Gefitinib
Iressa
EGFR2009CNSCLC
Gilteritinib
Xospata
FLT32018E*AML
Glasdegib
Daurismo
Hedgehog2018E*AML
Ibrutinib
Imbruvica
Bruton kinase2013DMantle cell lymphoma, CLL
Idelalisib
Zydelig
PI3Kδ2014DCLL, Non-Hodgkin lymphoma
Imatinib
Gleevec
BCR-ABL, c-Kit2001BCML, GIST
Ivosidenib
Tibsovo
Mutant IHD-12018E*AML
Ixazomib
Ninlaro
26S Proteasome2015E*Multiple myeloma
Lapatinib
Tykerb
EGFR, HER22007DBreast cancer, HER2 positive
Larotrectinib
Vitrakvi
NTRK2018E*Solid tumors
Lenvatinib
Lenvima
VEGFR 1-3, FGF 1-4, PDGF, c-Kit, RET2015
2016
2018
DThyroid cancer
Renal cell cancer
Hepatocellular cancer
Lorlatinib
Lorbrena
ALK2018E*NSCLC
Midostaurin
Rydapt
FLT32018E*AML
Neratinib
Nerlynx
HER22017E*Breast cancer
Nilotinib
Tasigna
BCR-ABL2007E*CML, resistant
Niraparib
Zejula
PARP2017E*Ovarian cancer
Olaparib
Lynparza
PARP2014
2018
EOvarian cancer
Advanced breast cancer
Osimertinib
Tagrisso
EGFR2015E*NSCLC, refractory
Palbociclib
Ibrance
ER+, HER22015E*Breast cancer, HER2 negative
Pazopanib
Votrient
VEGFR 1-32009CRenal cell cancer
Ponatinib
Iclusig
BCR-ABL2013E*CML, ALL
Regorafenib
Stivarga
VEGFR 1-3, PDGF2012DColorectal cancer, GIST
Ribociclib
Kisqali
Cyclin dependent kinase 4/62017CBreast cancer
Rucaparib
Rubraca
PARP2016D*Ovarian cancer, advanced
Ruxolitinib
Jakafi
Janus kinase2011E*Myelofibrosis
Sonidegib
Odomzo
Hedgehog2015E*Basal cell skin cancer
Sorafenib
Nexavar
VEGFR 1-32005
2007
2013
CRenal cell cancer
Hepatocellular cancer
Thyroid cancer
Sunitinib
Sutent
PDGF, c-Kit2006DCML, resistant; GIST, renal cell cancer
Talazoparib
Talzenna
PARP2018E*Breast cancer
Trametinib
Mekinist
MEK 1-22013E*Melanoma
Vandetanib
Caprelsa
VEGFR 22011E*Medullary thyroid cancer
Vemurafenib ZelborafBRAF2011E*Melanoma
Vismodegib
Erivedge
Hedgehog2012DBasal cell skin cancer
MISCELLANEOUS
Generic Name Brand Name Kinase
Target
ApprovalLikelihood
Score
Major Uses
Baricitinib
Olumiant
Janus kinase2018E*Rheumatoid arthritis
Fostamatinib TavalisseSpleen tyrosine kinase2017E*Immune thrombocytopenia
Nintedanib
Ofev
VEGFR, FGFR, PDGFR2014E*Pulmonary fibrosis
Pegaptanib
Macugen
VEGFR 1-32004EMacular degeneration
Tofacitinib
Xeljanz
Janus kinase2012E*Rheumatoid arthritis

Likelihood Score indicates the likelihood of association with drug induced liver injury,

based upon the known potential of the drug to cause such injury.

Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CLL,

chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; GIST, gastrointestinal

stromal tumor; NSCLC, non-small cell lung cancer.

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