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Cited by 574Protein Kinase Regulation and GTPase SignalingCancer Mechanisms and TherapyComputational Drug Discovery Methods

Properties of FDA-approved small molecule protein kinase inhibitors

Roskoski, Robert·2019·Pharmacological Research
DOI 10.1016/j.phrs.2019.03.006
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Abstract

Because mutations, overexpression, and dysregulation of protein kinases play essential roles in the pathogenesis of many illnesses, this enzyme family has become one of the most important drug targets in the past 20 years. The US FDA has approved 48 small molecule protein kinase inhibitors, nearly all of which are orally effective with the exceptions of netarsudil (which is given as an eye drop) and temsirolimus (which is given intravenously). Of the 48 approved drugs, the majority (25) target receptor protein-tyrosine kinases, ten target non-receptor protein-tyrosine kinases, and 13 target protein-serine/threonine protein kinases. The data indicate that 43 of these drugs are used in the treatment of malignancies (36 against solid tumors including lymphomas and seven against non-solid tumors, e.g., leukemias). Seven drugs are used in the treatment of non-malignancies: baricitinib, rheumatoid arthritis; fostamatinib, chronic immune thrombocytopenia; ruxolitinib, myelofibrosis and polycythemia vera; nintedanib, idiopathic pulmonary fibrosis; sirolimus, renal graft vs. host disease; netarsudil, glaucoma; tofacitinib, rheumatoid arthritis, Crohn disease, and ulcerative colitis. Moreover, ibrutinib and sirolimus are used for the treatment of both malignant and non-malignant diseases. The most common drug targets include ALK, B-Raf, BCR-Abl, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptor (VEGFR). Most of the small molecule inhibitors (45) interact directly with the protein kinase domain. In contrast, sirolimus, temsirolimus, and everolimus are larger molecules (MW ≈ 1000) that bind to FKBP-12 to generate a complex that inhibits mTOR (mammalian target of rapamycin). This review presents the available drug-enzyme X-ray crystal structures for 27 of the approved drugs as well as the chemical structures and physicochemical properties of all of the FDA-approved small molecule protein kinase antagonists. Six of the drugs bind covalently and irreversibly to their target. Twenty of the 48 drugs have molecular weights greater than 500, exceeding a Lipinski rule of five criterion. Excluding the macrolides (everolimus, sirolimus, temsirolimus), the average molecular weight of drugs is 480 with a range of 306 (ruxolitinib) to 615 (trametinib). Nearly half of the antagonists (23) have a lipophilic efficiency with values of less than five while the recommended optima range from 5-10. One of the vexing problems is the near universal development of resistance that is associated with the use of small molecule protein kinase inhibitors for the treatment of cancer.

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Authors
Roskoski, R.
Corresponding author
Roskoski, Robert
ORCID
Roskoski, Robert
Venue
Pharmacological Research
Publisher
Elsevier BV
Published
2019-06
Volume
144
Pages
19-50
ISSN
1043-6618 (ISSN-L)
DOI
10.1016/j.phrs.2019.03.006
OpenAlex
W2922159934
Cited by
554
References
225
Citations by year
2026: 36 · 2025: 42 · 2024: 60 · 2023: 43 · 2022: 64 · 2021: 153 · 2020: 109 · 2019: 47
FWCI
8.52
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Pharmacological Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords
protein kinase inhibitors, small-molecule kinase inhibitors, FDA-approved drugs, physicochemical properties, molecular weight, Lipinski's rule of five, kinase domain, mTOR inhibition, rapamycin, temsirolimus, everolimus, receptor tyrosine kinase, non-receptor tyrosine kinase, serine/threonine kinase
MeSH terms
Animals, Humans, Models, Molecular, Protein Conformation, Protein Kinases, United States, United States Food and Drug Administration, Drug Approval, Crystallography, X-Ray, Protein Kinase Inhibitors, Small Molecule Libraries, Molecular Targeted Therapy

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