Skip Navigation

DRUG RECORD

 

KINASE INHIBITORS

OVERVIEW
Protein Kinase Inhibitors

 

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

Approval

Likelihood

Score

Major Uses
Abemaciclib
Verzenio
Cyclin dependent  kinase 4/6 2017 E* Breast cancer
Acalabrutinib Calquence Bruton kinase 2017 D Mantel cell lymphoma
Afatinib
Gilotrif

EGFR, HER2

2013 D NSCLC
Alectinib
Alecensa

ALK

2015 D NSCLC
Axitinib
Inlyta

VEGFR 1-3

2012 E Renal cell cancer
Bortezomib
Velcade
Proteasome 2003 C Multiple myeloma, Mantle cell lymphoma
Bosutinib
Bosulif
BCR-ABL, scr 2012 E* CML, resistant
Brigatinib
Alunbrig
ALK 2017 E* NSCLC
Cabozantinib Cometriq, Cabometyx MET, VEGFR-2 2012 E* Medullary thyroid cancer, Renal cell cancer
Carfilzomib
Kyprolis
Proteasome 2012 E* Multiple myeloma, resistant
Ceritinib
Zykadia
ALK 2014 D NSCLC
Cobimetinib
Cotellic
MEK 2015 D Malignant melanoma
Copanlisib
Aliqopa
PI3Kα/δ 2017 E* Follicular lymphoma
Crizotinib
Xalkori
ALK 2011 D NSCLC
Dabrafenib
Tafinlar
BRAF 2013 E* Melanoma
Dasatinib
Sprycel
BCR-ABL, src 2006 D CML, resistant
Enasidenib
IDHIFA
Mutant IDH-2 2017 E* AML
Erlotinib
Tarceva
EGFR, HER1 2004 C NSCLC, Pancreatic cancer
Gefitinib
Iressa
EGFR 2009 C NSCLC
Ibrutinib
Imbruvica
Bruton kinase 2013 D Mantle cell lymphoma, CLL
Idelalisib
Zydelig
PI3Kδ 2014 D CLL, Non-Hodgkin lymphoma
Imatinib
Gleevec
BCR-ABL, c-Kit 2001 B CML, GIST
Ivosidenib
Tibsovo
 Mutant IHD-1 2018 E* AML
Ixazomib
Ninlaro
26S Proteasome 2015 E* Multiple myeloma
Lapatinib
Tykerb
EGFR, HER2 2007 D Breast cancer, HER2 positive

Lenvatinib

Lenvima

VEGFR 1-3, FGF 1-4, PDGF, c-Kit, RET

2015

2016

2018

D

Thyroid cancer

Renal cell cancer

Hepatocellular cancer

Neratinib
Nerlynx
HER2 2017 E* Breast cancer
Nilotinib
Tasigna
BCR-ABL 2007 E* CML, resistant
Niraparib
Zejula
PARP 2017 E* Ovarian cancer
Olaparib
Lynparza
PARP

2014

2018

E

Ovarian cancer

Advanced breast cancer

Osimertinib
Tagrisso
EGFR 2015 E* NSCLC, refractory
Palbociclib
Ibrance
ER+, HER2 2015 E* Breast cancer, HER2 negative
Pazopanib
Votrient
VEGFR 1-3 2009 C Renal cell cancer
Ponatinib
Iclusig
BCR-ABL 2013 E* CML, ALL

Regorafenib

Stivarga

VEGFR 1-3, PDGF 2012 D Colorectal cancer, GIST
Ribociclib
Kisqali
Cyclin dependent kinase 4/6 2017 C Breast cancer
Rucaparib
Rubraca
PARP 2016 D* Ovarian cancer, advanced
Ruxolitinib
Jakafi
Janus kinase 2011 E* Myelofibrosis
Sonidegib
Odomzo
Hedgehog 2015 E* Basal cell skin cancer
Sorafenib
Nexavar
VEGFR 1-3

2005

2007

2013

C

Renal cell cancer

Hepatocellular cancer

Thyroid cancer

Sunitinib
Sutent
PDGF, c-Kit 2006 D CML, resistant; GIST, renal cell cancer
Trametinib
Mekinist
MEK 1-2 2013 E* Malignant melanoma

Vandetanib

Caprelsa

VEGFR 2 2011 E* Medullary thyroid cancer
Vemurafenib Zelboraf BRAF 2011 E* Malignant melanoma
Vismodegib
Erivedge
Hedgehog 2012 D Basal cell skin cancer
MISCELLANEOUS
Generic Name   Brand Name  Kinase

Target

Approval

Likelihood

Score

Major Uses
Baricitinib
Olumiant
Janus kinase 2018 E* Rheumatoid arthritis
Fostamatinib Tavalisse Spleen tyrosine kinase 2017 E* Immune thrombocytopenia
Nintedanib
Ofev
VEGFR, FGFR, PDGFR 2014 E* Pulmonary fibrosis

Pegaptanib

Macugen

VEGFR 1-3 2004 E Macular degeneration
Tofacitinib
Xeljanz
Janus kinase 2012 E* 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.

 

Top of page