From the Blue Ridge Institute for Medical Research in Horse Shoe, North Carolina USA

USFDA approved protein kinase inhibitors compiled by Robert Roskoski Jr.

(Latest updates: Ibrutinib 15 January 2015, palbociclib 3 February 2015, lenvatinib on 13 February 2015, gefitinib on 13 July 2015)

Structurea, name, trade name, company, formula, molecular wt. The figures are drawn is such a fashion that the left-most portion of the drug extends toward or into the solvent, and the right side of the molecule interacts with hinge residues and hydrophobic components of target protein kinases, except for everolimus, sirolimus, and temsirolimus which bind to FKBP12 and indirectly inhibit mTOR. All drugs are effective orally, except for temsirolimus which is given intravenously. 

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D/Ab c Log Pc c Log Dd Yeare Known

targets

Indicationsf FDA Label
2/8 3.97 3.02 2013 EGFR, ErbB2, ErbB4 NSCLC

For the label click here

2/5 3.82 3.81 2012 VEGFR1/2/3, PDGFRβ RCC

For the label click here

1/8 4.96 4.12 2012 BCR-Abl, Src, Lyn, Hck CML

For the label click here

2/8 4.47 4.29 2012 RET, Met, VEGFR1/2/3, Kit, TrkB, Flt3, Axl, Tie2 Metastatic medullary thyroid cancer

For the label click here

3/8 6.087 3.89 2014 ALK, IGF-1R, InsR, ROS1 ALK-positive NSCLC after crizotinib resistance

For the label click here

3/6 4.39 2.66 2011 ALK, c-Met (HGFR), ROS, MST1R ALK-positive NSCLC For the label click here

3/7 4.51 2.64 2013 B-Raf Melanoma with BRAF mutations For the label click here
3/9 2.97 2.81 2006 BCR-Abl, Src, Lck, Yes, Fyn, Kit, EphA2, PDGFRβ Ph+ CML, ALL For the label click here
1/7 3.14 3.12 2004 EGFR NSCLC and pancreatic cancer For the label click here
3/15 4.47 4.47 2009 FKBP12/mTOR HER2-negative breast cancer, PNET, RCC, RAML, SEGA For the label click here

Approval withdrawn in the USA, but it is approved in dozens of countries. US FDA approval reinstated 15 July 2015.

1/7 4.50 4.33 2003-2005, 2015 EGFR NSCLC For the label click here
2/8 3.12 3.12 2013 Bruton's kinase Mantle cell lymphoma,  CLL, Waldenstrom's macroglobulinemia For the label click here
2/8 4.00 2.96 2001 BCR-Abl, Kit, PDGFR Ph+ CML or ALL, aggressive systemic mastocytosis, CEL, DFSP, HES, GIST, MDS/MDP For the label click here
2/8 4.97 4.92 2007 EGFR, ErbB2 Breast cancer For the label click here
4/8 3.57 3.56 2015 VEGFRs, FGFRs,

PDGFR, Kit, RET

Thyroid cancer For the label click here
2/8 4.96 4.48 2007 BCR-Abl, PDGFR, DDR1 Ph+ CML For the label click here
2/9 3.94 3.149 2014 FGFR1/2/3, PDGFRα/β, VEGFR1/2/3, Flt3 Idiopathic pulmonary fibrosis For the label click here
2/8 0.299 1.872 2015 CDK4/6 ER+ and HER2 breast cancer For the label click here
3/9 3.81 3.18 2009 VEGFR1/2/3, PDGFRα/β, FGFR1/3, Kit, Lck, Fms, Itk RCC, soft tissue sarcomas For the label click here
1/7 4.68 3.83 2012 BCR-Abl, BCR-Abl T315I, VEGFR, PDGFR, FGFR, EphR, Src family kinases, Kit, RET, Tie2, Flt3 Ph+ CML or ALL For the label click here
3/7 4.80 4.74 2012 VEGFR1/2/3, BCR-Abl, B-Raf, B-Raf(V600E), Kit, PDGFRα/β, RET, FGFR1/2, Tie2, 
Eph2A
CRC For the label click here
1/6 2.02 2.02 2011 JAK1/2 Myelofibrosis and PV For the label click here
3/14 4.46 4.46 1999 FKBP12/mTOR Renal transplant, lymphangioleiomyomatosis For the label click here
3/7 4.61 4.59 2005 B/C-Raf, B-Raf (V600E), Kit, Flt3, RET, VEGFR1/2/3, PDGFRβ Hepatocellular carcinoma, RCC, DTC For the label click here
3/6 3.17 1.68 2006 PDGFRα/β, VEGFR1/2/3, Kit, Flt3, CSF-1R, RET RCC, GIST, PNET For the label click here
1/7 1.006 - 0.02 2012 JAK1/3 Rheumatoid arthritis For the label click here
4/17 4.29 4.29 2007 FKBP12/mTOR Advanced RCC For the label click here

2/9 3.41 3.41 2013 MEK1/2 Melanoma For the label click here
1/6 5.34 3.89 2011 EGFRs, VEGFRs, RET, Brk, Tie2, EphRs, Src family kinases Medullary thyroid cancer For the label click here
2/6 4.85 3.38 2011 A/B/C-Raf, B-Raf (V600E), SRMS, ACK1, MAP4K5, FGR Melanoma with BRAFV600E mutation

For the label click here

aStructures drawn with Accelrys Draw 4.1, Accelrys, Inc. San Diego, CA 92121. In those cases for which the crystal structure of the protein kinase bound to the drug is known, the right side of the molecule occurs in the ATP-binding pocket and the left side of the molecule extends into the solvent. For cabozantinib, dabrafenib, ibrutinib, levatinib, palbociclib, regorafenib, ruxolitinib, tofacitinib, trametinib, and vandetanib, this mode of binding is inferred, but not experimentally established. 

bD, number of hydrogen bond donors; A, number of hydrogen bond acceptors.

cCalculated log of the partition coefficient; dCalculated log of the distribution coefficient. Both calculations performed with MedChem DesignerTM, version 2.0, Simulationsplus, Inc. Lancaster, CA 93534. The partition coefficient is the ratio of a compounds solubility in octanol/water at pH 7.4. The distribution coefficient is this solubility where pH is not taken into account.

eYear approved Aftatinib, Axitinib, Bosutinib, Cabozantinib, Crizotinib, Dabrafenib, Dasatinib, Erlotinib, Everolimus, Gefitinib, Ibrutinib, Imatinib, Lapatinib, Nilotinib, Nintedanib, Pazopanib

fALL, acute lymphoblastic leukemia, CEL, chronic eosinophilic leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CRC, colorectal cancer; DDR1, Discoidin domain receptor family, member 1; DFSP, dermatofibrosarcoma protuberans; DTC, differentiated thyroid carcinoma; GIST, gastrointestinal stromal tumor; HES, hypereosinophilic syndrome, HGFR, hepatocyte growth factor recepter; MDS/MDP, myelodisplastic/myeloproliferative diseases; MST1R, macrophage-stimulating protein receptor aka RON (Recepteur d'Origine Nantais); NSCLC, non-small cell lung cancer; PNET, progressive neuroendocrine tumors of pancreatic origin; Ph+, Philadelphia chromosome positive;  PV, polycythemia vera; RAML, renal angiomyolipoma; RCC, renal cell carcinoma; SEGA, subependymal giant cell astrocytoma. See the drug label for specifics. For example, one indication for everolimus is for postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole. Ponatinib, Regorafenib, Ruxolitinib, Sirolimus, Sorafenib, Sunitinib, Temsirolimus, Tofacitinib, Temsirolimus, Trametinib, Vandetanib, Vemurafenib

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Posted 9 December 2012 and updated 19 July 2015

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