From the Blue Ridge Institute for Medical Research in Horse Shoe, NC

USFDA approved protein kinase inhibitors (Nintedanib 16 October 2014) compiled by Robert Roskoski Jr.

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 NSCLC

For the label click here

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

For the label click here

1/8 4.96 4.12 2012 BCR-Abl, Src, Lyn, and 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), and Ros ALK-positive NSCLC For the label click here

3/7 4.51 2.64 2013 B-RAF Melanoma For the label click here
3/9 2.97 2.81 2006 BCR-Abl, Src, Lck, Yes, Fyn, Kit, EphA2, and PDGFRβ CML 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 Progressive neuroendocrine tumors of pancreatic origin, RCC, subependymal giant cell astrocytoma, breast cancer For the label click here

Approval withdrawn in the USA, but it is approved in dozens of countries

1/7 4.50 4.33 2003 EGFR NSCLC For the label click here
2/8 3.12 3.12 2013 Bruton's kinase Mantle cell lymphoma and CLL (updated 20 February 2014) For the label click here
2/8 4.00 2.96 2003 BCR-Abl, Kit, and PDGFR CML, ALL, aggressive systemic mastocytosis, GIST For the label click here
2/8 4.97 4.92 2007 EGFR and ErbB2 Breast cancer For the label click here
2/8 4.96 4.48 2007 BCR-Abl, PDGFR CML For the label click here
2/9 3.94 3.149 2014 VEGFR, FGFR, PDGFR Idiopathic pulmonary fibrosis Not yet available
3/9 3.81 3.18 2009 VEGFR1/2/3, PDGFRα/β, FGFR1/3, Kit, Lck, Fms, and Itk RCC, soft tissue sarcomas For the label click here

Ariad suspended sales on 30 October 2013 because of serious side effects. Sales will resume and the new label warns of its possible side effects (20 December 2013).

1/7 4.68 3.83 2012 BCR-Abl, BCR-Abl T315I, VEGFR, PDGFR, FGFR, Eph, Src family kinases, Kit, RET, Tie2, and Flt3 CML, Ph chromosome positive 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, and
Eph2A
CRC For the label click here
1/6 2.02 2.02 2011 JAK1/2 Myelofibrosis For the label click here
3/14 4.46 4.46 1999 FKBP12/mTOR Renal transplant For the label click here
3/7 4.61 4.59 2005 C-Raf, B-Raf, B-Raf (V600E), Kit, Flt3, RET, VEGFR1/2/3, and PDGFRα/β Hepatocellular carcinoma, RCC, DTC (updated 23 Nov 2013) For the label click here
3/6 3.17 1.68 2006 PDGFRα/β, VEGFR1/2/3, Kit, Flt3, CSF-1R, and RET RCC, GIST, pancreatic neuroendocrine tumors For the label click here
1/7 1.006 - 0.02 2012 JAK3 Rheumatoid arthritis For the label click here
4/17 4.29 4.29 2007 FKBP12/mTOR 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, and Src family kinases Medullary thyroid cancer For the label click here
2/6 4.85 3.38 2011 A/B/C-Raf and B-Raf (V600E) 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, 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, CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CRC, colorectal cancer; DTC, differentiated thyroid carcinoma; GIST, gastrointestinal stromal tumor; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma. 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 6 April 2014

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