Kinase inhibitors

Kinase inhibitors

Protein and (lipid kinases) represent an important target class for treating human disorders, as their aberrant activity underlies a variety of pathologies, ranging from cancer, inflammatory diseases, diabetes, infectious diseases, and cardiovascular disorders.

To date more than 35 small molecule protein kinase inhibitors have been approved for human use around the world. The majority of these are for oncology indications, but a growing number are targeting immune-related conditions such as rheumatoid arthritis (tofacitinib, a Janus kinase 3 inhibitor). Two earlier inhibitors, sirolimus and everolimus (mTOR inhibitors) are used as immunosuppressants to reduce rejection of transplanted organs. Subsequently everolimus has been approved for oncology use, for the treatment of progressive, well-differentiated non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin, in patients with unresectable, locally advanced or metastatic disease.

Approved kinase inhibitors (worldwide)

INN Target/s Indication/s Year first approved
fasudil ROCK (ROCK1 & ROCK2) cerebral vasospasm 1995- China & Japan only
sirolimus mTOR kidney transplants 1999
imatinib  ABL, PDGFR (alpha & beta), KIT CML, Ph+ B-ALL, CMML, HES, GIST 2001
gefitinib EGFR NSCLC 2003
erlotinib EGFR NSCLC, pancreatic cancer 2004
sorafenib  VEGFR2, PDGFR (alpha & beta), KIT, FLT3, BRAF RCC, HCC 2005
sunitinib  VEGFR1, VEGFR2 & VEGFR3, KIT, PDGFR (alpha & beta) , RET, CSF1R, FLT3   RCC, imatinib resistant GIST 2006
dasatinib  ABL, PDGFR (alpha & beta), KIT, SRC  CML 2007
lapatinib EGFR, ERBB2 BC 2007
nilotinib  ABL, PDGFR (alpha & beta), KIT CML 2007
everolimus  mTOR RCC, SEGA, transplantation  2009
temsirolimus  mTOR RCC 2009
axitinib VEGFR1, VEGFR2 & VEGFR3, KIT, PDGFR (alpha & beta), RET, CSF1R, FLT3 RCC 2011
ruxolitinib JAK2 IMF with JAK2V617F 2011
vemurafenib BRAF m-Melanoma with BRAFV600E 2011
crizotinib  MET, ALK  NSCLC with ALK translocations 2011
tofacitinib JAK3 RA 2012
pazopanib VEGFR1, VEGFR2 & VEGFR3, PDGFR (alpha & beta), KIT RCC 2012
bosutinib ABL  CML resistant/ intolerant to therapy 2012
cabozantinib VEGFR2, PDGFR (alpha & beta), KIT, FLT3 MTC 2012
ponatinib ABL T315 resistant CML 2012
regorafenib VEGFR2, Tie2 CRC, GIST 2012
afatinib EGFR NSCLC with EGFR activating mutations  2013
dabrafenib BRAF m-Melanoma with BRAFV600E 2013
trametinib  MEKs m-Melanoma with BRAFV600E 2013
ibrutinib BTK MCL  2013
nintedanib VEGFR1, VEGFR2 & VEGFR3, PDGFR (alpha & beta), FGFRs IPF 2014
idelalisib   PI3Kδ leukemia and lymphomas 2014
ceritinib ALK NSCLC with ALK translocations 2014
alectinib ALK ALK-rearranged NSCLC 2014- FDA 2015
cobimetinib MEK1 & MEK2 melanoma, BC, other solid tumours 2015
lenvatinib VEGFR1, VEGFR2 & VEGFR3 progressive, differentiated thyroid cancer, advanced renal cell carcinoma (in combination with everolimus) 2015
palbociclib CDK4 & 6 advanced (metastatic) BC 2015
radotinib BRC- ABL & PDGFR (alpha & beta) CML 2015-S Korea only
osimertinib mutant EGFR  T790M +ve NSCLC 2015
brigatinib ALK, EGFR  ALK-rearranged metastatic NSCLC, resistant to crizotinib 2017

Disease abbreviations: BC (breast cancer), CMML (chronic myelomonocytic leukaemia), CML (chronic myeloid leukaemia), CRC (colorectal cancer), GIST (gastrointestinal cancer), HES (hypereosinophilic syndrome), IPF (idiopathic pulmonary fibrosis), MCL (Mantle cell lymphoma), MTC (medullary thyroid cancer), NSCLC (non-small cell lung cancer), Ph+ B-ALL (Philadelphia chromosome positive acute lymphoblastic leukemia), RA (rheumatoid arthritis), RCC (renal cell carcinoma), SEGA (subependymal giant cell astrocytoma)

lipid kinases, protein kinases

25 years of small molecular weight kinase inhibitors: potentials and limitations.

A review of the progress and achievements made using kinase inhibitors to treat a wide variety of diseases, plus discussion of the future potential of these small molecules.

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Ten things you should know about protein kinases: IUPHAR Review 14.

This review article presents a brief history of kinase research and inhibitor development, highlighting landmarks in the drug discovery process and pointing to the limitations of their use.

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