| Structural highlights
Disease
[CSF1R_HUMAN] Note=Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers.[1] [2] [3] [4] [5] [6] Note=Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection.[7] [8] [9] [10] [11] [12] Defects in CSF1R are the cause of leukoencephalopathy, diffuse hereditary, with spheroids (HDLS) [MIM:221820]. An autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes.[13] [14] [15] [16] [17] [18] [19]
Function
[CSF1R_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor.[20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]
Publication Abstract from PubMed
DNA-PK is a key component within the DNA damage response, as it is responsible for recognizing and repairing double-strand DNA breaks (DSBs) via non-homologous end joining. Historically it has been challenging to identify inhibitors of the DNA-PK catalytic subunit (DNA-PKcs) with good selectivity versus the structurally related PI3 (lipid) and PI3K-related protein kinases. We screened our corporate collection for DNA-PKcs inhibitors with good PI3 kinase selectivity, identifying compound 1. Optimization focused on further improving selectivity whilst improving physical and pharmacokinetic properties, notably co-optimization of permeability and metabolic stability, to identify compound 16 (AZD7648). Compound 16 had no significant off-targets in the protein kinome, and only weak activity versus PI3Kalpha/gamma lipid kinases. Monotherapy activity in murine xenograft models was observed, and regressions were observed when combined with inducers of DSBs (doxorubicin or irradiation) or PARP inhibition (olaparib). These data support progression into clinical studies (NCT03907969).
The discovery of 7-methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-p yran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor.,Goldberg FW, Finlay MRV, Ting A, Beattie D, Lamont G, Fallan C, Wrigley G, Schimpl M, Howard MR, Williamson B, Vazquez-Chantada M, Barratt D, Davies B, Cadogan E, Ramos Montoya A, Dean E J Med Chem. 2019 Dec 18. doi: 10.1021/acs.jmedchem.9b01684. PMID:31851518[34]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. PMID:15117969 doi:10.1083/jcb.200309102
- ↑ Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. PMID:16648572 doi:10.1158/1535-7163.MCT-05-0359
- ↑ Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T, Isoe T. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43. PMID:17121910 doi:10.1158/1535-7163.MCT-05-0313
- ↑ Hiraga T, Nakamura H. Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals. Int J Cancer. 2009 Jan 1;124(1):215-22. doi: 10.1002/ijc.23903. PMID:18814279 doi:10.1002/ijc.23903
- ↑ Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009 Dec 15;69(24):9498-506. doi: 10.1158/0008-5472.CAN-09-1868. Epub, . PMID:19934330 doi:10.1158/0008-5472.CAN-09-1868
- ↑ Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Epub 2005 Dec 6. PMID:16337366 doi:10.1016/j.coi.2005.11.006
- ↑ Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. PMID:15117969 doi:10.1083/jcb.200309102
- ↑ Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. PMID:16648572 doi:10.1158/1535-7163.MCT-05-0359
- ↑ Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T, Isoe T. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43. PMID:17121910 doi:10.1158/1535-7163.MCT-05-0313
- ↑ Hiraga T, Nakamura H. Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals. Int J Cancer. 2009 Jan 1;124(1):215-22. doi: 10.1002/ijc.23903. PMID:18814279 doi:10.1002/ijc.23903
- ↑ Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009 Dec 15;69(24):9498-506. doi: 10.1158/0008-5472.CAN-09-1868. Epub, . PMID:19934330 doi:10.1158/0008-5472.CAN-09-1868
- ↑ Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Epub 2005 Dec 6. PMID:16337366 doi:10.1016/j.coi.2005.11.006
- ↑ Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. PMID:15117969 doi:10.1083/jcb.200309102
- ↑ Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. PMID:16648572 doi:10.1158/1535-7163.MCT-05-0359
- ↑ Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T, Isoe T. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43. PMID:17121910 doi:10.1158/1535-7163.MCT-05-0313
- ↑ Hiraga T, Nakamura H. Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals. Int J Cancer. 2009 Jan 1;124(1):215-22. doi: 10.1002/ijc.23903. PMID:18814279 doi:10.1002/ijc.23903
- ↑ Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009 Dec 15;69(24):9498-506. doi: 10.1158/0008-5472.CAN-09-1868. Epub, . PMID:19934330 doi:10.1158/0008-5472.CAN-09-1868
- ↑ Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Epub 2005 Dec 6. PMID:16337366 doi:10.1016/j.coi.2005.11.006
- ↑ Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, Lash J, Wider C, Wojtas A, DeJesus-Hernandez M, Adamson J, Kouri N, Sundal C, Shuster EA, Aasly J, MacKenzie J, Roeber S, Kretzschmar HA, Boeve BF, Knopman DS, Petersen RC, Cairns NJ, Ghetti B, Spina S, Garbern J, Tselis AC, Uitti R, Das P, Van Gerpen JA, Meschia JF, Levy S, Broderick DF, Graff-Radford N, Ross OA, Miller BB, Swerdlow RH, Dickson DW, Wszolek ZK. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet. 2011 Dec 25;44(2):200-5. doi: 10.1038/ng.1027. PMID:22197934 doi:10.1038/ng.1027
- ↑ Bourette RP, Mouchiroud G, Ouazana R, Morle F, Godet J, Blanchet JP. Expression of human colony-stimulating factor-1 (CSF-1) receptor in murine pluripotent hematopoietic NFS-60 cells induces long-term proliferation in response to CSF-1 without loss of erythroid differentiation potential. Blood. 1993 May 15;81(10):2511-20. PMID:7683918
- ↑ Baran CP, Tridandapani S, Helgason CD, Humphries RK, Krystal G, Marsh CB. The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity. J Biol Chem. 2003 Oct 3;278(40):38628-36. Epub 2003 Jul 25. PMID:12882960 doi:10.1074/jbc.M305021200
- ↑ Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. PMID:15117969 doi:10.1083/jcb.200309102
- ↑ Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. PMID:16648572 doi:10.1158/1535-7163.MCT-05-0359
- ↑ Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T, Isoe T. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43. PMID:17121910 doi:10.1158/1535-7163.MCT-05-0313
- ↑ Taylor JR, Brownlow N, Domin J, Dibb NJ. FMS receptor for M-CSF (CSF-1) is sensitive to the kinase inhibitor imatinib and mutation of Asp-802 to Val confers resistance. Oncogene. 2006 Jan 5;25(1):147-51. PMID:16170366 doi:10.1038/sj.onc.1209007
- ↑ Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E, Halenbeck R, Wu G, Zhou A, Behrens D, Hollenbaugh D, Linnemann T, Qin M, Wong J, Chu K, Doberstein SK, Williams LT. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science. 2008 May 9;320(5877):807-11. doi: 10.1126/science.1154370. PMID:18467591 doi:10.1126/science.1154370
- ↑ Hiraga T, Nakamura H. Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals. Int J Cancer. 2009 Jan 1;124(1):215-22. doi: 10.1002/ijc.23903. PMID:18814279 doi:10.1002/ijc.23903
- ↑ Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009 Dec 15;69(24):9498-506. doi: 10.1158/0008-5472.CAN-09-1868. Epub, . PMID:19934330 doi:10.1158/0008-5472.CAN-09-1868
- ↑ Chihara T, Suzu S, Hassan R, Chutiwitoonchai N, Hiyoshi M, Motoyoshi K, Kimura F, Okada S. IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation. Cell Death Differ. 2010 Dec;17(12):1917-27. doi: 10.1038/cdd.2010.60. Epub 2010, May 21. PMID:20489731 doi:10.1038/cdd.2010.60
- ↑ Eda H, Zhang J, Keith RH, Michener M, Beidler DR, Monahan JB. Macrophage-colony stimulating factor and interleukin-34 induce chemokines in human whole blood. Cytokine. 2010 Dec;52(3):215-20. doi: 10.1016/j.cyto.2010.08.005. Epub 2010 Sep, 9. PMID:20829061 doi:10.1016/j.cyto.2010.08.005
- ↑ Wei S, Nandi S, Chitu V, Yeung YG, Yu W, Huang M, Williams LT, Lin H, Stanley ER. Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol. 2010 Sep;88(3):495-505. doi: 10.1189/jlb.1209822. Epub 2010 May, 26. PMID:20504948 doi:10.1189/jlb.1209822
- ↑ Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Epub 2005 Dec 6. PMID:16337366 doi:10.1016/j.coi.2005.11.006
- ↑ Huang H, Hutta DA, Rinker JM, Hu H, Parsons WH, Schubert C, Desjarlais RL, Crysler CS, Chaikin MA, Donatelli RR, Chen Y, Cheng D, Zhou Z, Yurkow E, Manthey CL, Player MR. Pyrido[2,3-d]pyrimidin-5-ones: A Novel Class of Antiinflammatory Macrophage Colony-Stimulating Factor-1 Receptor Inhibitors (dagger). J Med Chem. 2009 Feb 4. PMID:19193011 doi:10.1021/jm801406h
- ↑ Goldberg FW, Finlay MRV, Ting A, Beattie D, Lamont G, Fallan C, Wrigley G, Schimpl M, Howard MR, Williamson B, Vazquez-Chantada M, Barratt D, Davies B, Cadogan E, Ramos Montoya A, Dean E. The discovery of 7-methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-p yran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor. J Med Chem. 2019 Dec 18. doi: 10.1021/acs.jmedchem.9b01684. PMID:31851518 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01684
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