PMID- 31862477 OWN - NLM STAT- MEDLINE DCOM- 20210104 LR - 20210104 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 152 DP - 2020 Feb TI - Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update. PG - 104609 LID - S1043-6618(19)32889-0 [pii] LID - 10.1016/j.phrs.2019.104609 [doi] AB - 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 approximately 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. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Roskoski, Robert Jr AU - Roskoski R Jr AD - Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, North Carolina, 28742-8814, United States. Electronic address: rrj@brimr.org. LA - eng PT - Journal Article PT - Review DEP - 20191217 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) SB - IM MH - Animals MH - Antineoplastic Agents/chemistry/classification/pharmacology/therapeutic use MH - Drug Approval MH - Humans MH - *Protein Kinase Inhibitors/chemistry/classification/pharmacology/therapeutic use MH - United States MH - United States Food and Drug Administration OTO - NOTNLM OT - Binimetinib (PubMED CID: 10288191) OT - Catalytic spine OT - Crizotinib (PubMED CID: 9033117) OT - Dabrafenib (PubMED CID: 44462760) OT - Entrectinib (PubMED CID: 25141092) OT - Erdafitinib (PubMED CID: 67462786) OT - Fedratinib (PubMED CID: 16722836) OT - Hydrophobic interaction OT - Imatinib (PubMED CID: 123596) OT - Pexidartinib (PubMED CID: 25151352) OT - Protein kinase inhibitor classification OT - Protein kinase structure OT - Regulatory spine OT - Shell residues OT - Sorafenib (PubMED CID: 216239) OT - Trametinib (PubMED CID: 11707110) COIS- Declaration of Competing Interest The author is unaware of any affiliations, memberships, or financial holdings that might be perceived as affecting the objectivity of this review. EDAT- 2019/12/22 06:00 MHDA- 2021/01/05 06:00 CRDT- 2019/12/22 06:00 PHST- 2019/12/14 00:00 [received] PHST- 2019/12/16 00:00 [accepted] PHST- 2019/12/22 06:00 [pubmed] PHST- 2021/01/05 06:00 [medline] PHST- 2019/12/22 06:00 [entrez] AID - S1043-6618(19)32889-0 [pii] AID - 10.1016/j.phrs.2019.104609 [doi] PST - ppublish SO - Pharmacol Res. 2020 Feb;152:104609. doi: 10.1016/j.phrs.2019.104609. Epub 2019 Dec 17.