Properties of FDA-approved small molecule protein kinase inhibitors: A 2021 update

Pharmacol Res. 2021 Mar:165:105463. doi: 10.1016/j.phrs.2021.105463. Epub 2021 Jan 26.


Owing to the dysregulation of protein kinase activity in many diseases including cancer, the protein kinase enzyme family has become one of the most important drug targets in the 21st century. There are 62 FDA-approved therapeutic agents that target about two dozen different protein kinases and eight of these were approved in 2020. All of the FDA-approved drugs are orally effective with the exception of netarsudil (a ROCK1/2 non-receptor protein-serine/threonine kinase antagonist given as an eye drop for the treatment of glaucoma) and temsirolimus (an indirect mTOR inhibitor given intravenously for the treatment of renal cell carcinoma). Of the approved drugs, ten target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), thirteen block non-receptor protein-tyrosine kinases, and 35 target receptor protein-tyrosine kinases. The data indicate that 55 of these drugs are prescribed for the treatment of neoplasms (52 against solid tumors including breast, lung, and colon, nine against non-solid tumors such as leukemias, and four against both solid and non-solid tumors: acalabrutinib, ibrutinib, imatinib, and midostaurin). A total of three drugs (baricitinib, tofacitinib, upadacitinib) is used for the treatment of inflammatory diseases including rheumatoid arthritis. Seven of the approved drugs form covalent bonds with their target enzymes and are classified as TCIs (targeted covalent inhibitors). Of the 62 approved drugs, eighteen are used in the treatment of multiple diseases. Imatinib, for example, is approved for the treatment of eight different disorders. The most common drug targets of the approved pharmaceuticals include BCR-Abl, B-Raf, vascular endothelial growth factor receptors (VEGFR), epidermal growth factor receptors (EGFR), and ALK. The following eight drugs received FDA approval in 2020 for the treatment of the specified diseases: avapritinib and ripretinib (gastrointestinal stromal tumors), capmatinib (non-small cell lung cancer), pemigatinib (cholangiocarcinoma), pralsetinib and selpercatinib (non-small cell lung cancer, medullary thyroid cancer, differentiated thyroid cancer), selumetinib (neurofibromatosis type I), and tucatinib (HER2-positive breast cancer). All of the eight drugs approved in 2020 fulfill Lipinski's rule of five criteria for an orally effective medicine (MW of 500 Da or less, five or fewer hydrogen bond donors, 10 or fewer hydrogen bond acceptors, calculated log10 of the partition coefficient of five or less) with the exception of three drugs with a molecular weight greater that 500 Da: pralsetinib (534), selpercatinib (526) and ripretinib (510). This review summarizes the physicochemical properties of all 62 FDA-approved small molecule protein kinase inhibitors.

Keywords: Avapritinib (PubMED CID: 118023034); Capmatinib (PubMED CID: 25145656); Catalytic spine; Hydrophobic interaction; Pemigatinib (PubMED CID: 86705659); Pralsetinib (PubMED CID: 129073603); Protein kinase inhibitor classification; Protein kinase structure; Regulatory spine; Ripretinib (PubMED CID: 71584930); Selpercatinib (PubMED CID: 134436906); Selumetinib (PubMED CID: 10127622); Shell residues; Tucatinib (PubMED CID: 51039094); Upadacitinib (PubMED CID: 58557659); Zanubrutinib (PubMED CID: 135565884).

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Drug Approval / methods*
  • Humans
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Structure, Secondary
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • United States
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • Vascular Endothelial Growth Factor A
  • pralsetinib