Because genetic alterations including mutations, overexpression, translocations, 
and dysregulation of protein kinases are involved in the pathogenesis of many 
illnesses, this enzyme family is currently the subject of many drug discovery 
programs in the pharmaceutical industry. The US FDA approved four small molecule 
protein kinase antagonists in 2019; these include entrectinib, erdafitinib, 
pexidartinib, and fedratinib. Entrectinib binds to TRKA/B/C and ROS1 and is 
prescribed for the treatment of solid tumors with NTRK fusion proteins and for 
ROS1-postive non-small cell lung cancers. Erdafitinib inhibits fibroblast growth 
factor receptors 1-4 and is used in the treatment of urothelial bladder cancers. 
Pexidartinib is a CSF1R antagonist that is prescribed for the treatment of 
tenosynovial giant cell tumors. Fedratinib blocks JAK2 and is used in the 
treatment of myelofibrosis. Overall, the US FDA has approved 52 small molecule 
protein kinase inhibitors, nearly all of which are orally effective with the 
exceptions of temsirolimus (which is given intravenously) and netarsudil (an eye 
drop). Of the 52 approved drugs, eleven inhibit protein-serine/threonine protein 
kinases, two are directed against dual specificity protein kinases, eleven 
target non-receptor protein-tyrosine kinases, and 28 block receptor 
protein-tyrosine kinases. The data indicate that 46 of these drugs are used in 
the treatment of neoplastic diseases (eight against non-solid tumors such as 
leukemias and 41 against solid tumors including breast and lung cancers; some 
drugs are used against both tumor types). Eight drugs are employed in the 
treatment of non-malignancies: fedratinib, myelofibrosis; ruxolitinib, 
myelofibrosis and polycythemia vera; fostamatinib, chronic immune 
thrombocytopenia; baricitinib, rheumatoid arthritis; sirolimus, renal graft vs. 
host disease; nintedanib, idiopathic pulmonary fibrosis; netarsudil, glaucoma; 
and tofacitinib, rheumatoid arthritis, Crohn disease, and ulcerative colitis. 
Moreover, sirolimus and ibrutinib are used for the treatment of both neoplastic 
and non-neoplastic diseases. Entrectinib and larotrectinib are tissue-agnostic 
anti-cancer small molecule protein kinase inhibitors. These drugs are prescribed 
for the treatment of any solid cancer harboring NTRK1/2/3 fusion proteins 
regardless of the organ, tissue, anatomical location, or histology type. Of the 
52 approved drugs, seventeen are used in the treatment of more than one disease. 
Imatinib, for example, is approved for the treatment of eight disparate 
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. Most of the approved small molecule 
protein kinase antagonists (49) bind to the protein kinase domain and six of 
them bind covalently. In contrast, everolimus, temsirolimus, and sirolimus are 
larger molecules (MW ≈ 1000) that bind to FK506 binding protein-12 (FKBP-12) to 
generate a complex that inhibits the mammalian target of rapamycin (mTOR) 
protein kinase complex. This review presents the physicochemical properties of 
all of the FDA-approved small molecule protein kinase inhibitors. Twenty-two of 
the 52 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 the approved drugs is 480 with a 
range of 306 (ruxolitinib) to 615 (trametinib). More than half of the 
antagonists (29) have lipophilic efficiency values of less than five while the 
recommended optima range from 5 to 10. One of the troublesome problems with both 
targeted and cytotoxic drugs in the treatment of malignant diseases is the near 
universal development of resistance to every therapeutic modality.