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  • The present review also summarizes the efforts that

    2020-01-14

    The present review also summarizes the efforts that have been made to find new c-FMS inhibitors under clinical trial as given in the Table 1. These inhibitors may reduce the burdens of potency and side effects that have faced the scientists globally. ABT-869 41 was manufactured in Abbott laboratories, USA, using structure based drug designing. It is the inhibitor of RTK, VEGFRs and PDGFR families. It has successfully completed phase I trial, proving better efficiency in solid tumours, including lung and hepatocellular carcinoma. Early phase data and ongoing phase II studies will be reviewed [135]. Imatinib 42 developed by Novartis is one of the first cancer therapies inhibiting the tyrosine kinases BCR-ABL, c-KIT and PDGFRA. From clinical trials, it is confirmed as a successful drug for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. At the cellular level, it binds close to the ATP binding site on tyrosine kinase thus inhibiting the enzymatic activity of protein [136]. AG013736 43 is the inhibitor of tyrosine kinase developed by Pfizer. It is found to be effective against breast cancer and renal cell carcinoma. It is the inhibitor of vascular endothelial growth factor receptor, c-KIT, PDGFR and also inhibit angiogenesis. It generally acts through autophagy, destruction of body Caffeine [137]. CHIR258 44 is the inhibitor of fibroblast growth factor receptor 3 (FGFR3) and also the inhibitor of class III, IV and V receptor tyrosine kinases (RTKs). Its Mechanism of action involves the inhibition of receptor kinase phosphorylation. It induces both cytostatic and cytotoxic effects [138]. SU11248 45 is a small receptor tyrosine kinase inhibitor, developed by SUGEN, involve the treatment of renal cell carcinoma, pancreatic tumors, and gastrointestinal stromal tumor by inhibiting cellular signalling by competing with ATP binding to the catalytic site of receptor tyrosine kinases [139]. Ki20227 46 is a highly selective c-FMS tyrosine kinase inhibitor manufactured by Kirin Pharma, Japan. It inhibits the M-CSF induced tumor necrosis factor-alpha production. In collagen induced model, it is found to inhibit inflammation and collagen induced osteolysis markedly reduced the arthritis and bone destruction [10]. GW2580 47 provided by Glaxo Smith Kline, UK, inhibit the TNF production from immune complex-stimulated macrophages and inhibit c-FMS induced arthritis. It is equivalent to imatinib in potency for reducing collagen induced arthritis, anti collagen antibody induced arthritis [140]. JNJ-28312141 (48) developed by Johnson & Johnson Pharmaceutical Research & Development, is a novel colony stimulating factor-1 and FMS related receptor tyrosine kinase inhibitors. It involves in the inhibition of solid tumors, bone metastases and acute myeloid leukemia [141]. PLX3397 49 is a potential CSF-1R inhibitor along with KIT and FLT-3, found to inhibit growth of synovial tumors. When tested in rodent model, it inhibits tumorigenesis associated with Breast carcinoma. It is tested in combination with various other drugs, i.e., paclitaxel, temozolomide, temozolomide, eribulin, pembrolizumab for cancer treatment [142]. JNJ-40346527 50 is a selective inhibitor of CSF-1R with high tolerability found to be beneficial in the treatment of Hodgkin lymphoma. It also prevents osteoclastogenesis in arthritis. 150–600 mg per day is the dose fixed for the inhibition of CSF-1R. The mechanism involves the CSF-1R of phosphorylation inhibition [143]. PLX647 51 block the CSF-1/CSF-1R signalling and alleviate immune suppression. There is a strong relationship between cancer and immune system, i.e., cancer evades the immune system and vice-versa. It is found to be used in the treatment of breast cancer, human melanoma and lung tumours, which is due to the expression of CSF-1/CSF-1R signalling [144]. Masitinib 52 developed by Howland et al., involve inhibition of receptor and non-receptor tyrosine kinases (c-KIT, platelet derived growth factor, fibroblast growth factor receptor) and controlling inflammation and exaggerated glial cell activation [145]. Pacritinib 53 used for the treatment of myelofibroisis, it both inhibit receptor and non-receptor tyrosine kinases. Hence have wide range of uses [146]. Propanib 54 is a potent multitargeting agent inhibits tumor growth and angiogenesis. It is a multikinase inhibitor such as c-KIT, FGFR (fibroblast growth factor receptor), PDGFR (platelet growth factor receptors) and VEGFR (vascular endothelial growth factor receptors) [147]. RXDX-105 55 is a potent inhibitor of RET, BRAF, endothelial growth factor controlling metastatic cancers [148]. CS2164 56 is a multitargeting agent. It inhibits VEGFR2, VEGFR2, VEGFR3, PDGFR and c-KIT induced angiogenesis, vasculature formation in tumor tissues, ligand dependant cell proliferation etc. Major role is suppression of chronic tumor. In-vivo study with breast cancer induced mice group proved that administration of CS2164 reduced the CSF-1R induced breast cancer symptoms [149].