PMC:7417114 / 62997-67085 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7417114","sourcedb":"PMC","sourceid":"7417114","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7417114","text":"ABL, PDGFR, and SRC inhibitors\nCytokine inhibition and anti-inflammatory and antifibrotic activity displayed by some inhibitors of Abelson murine leukemia viral oncogene homolog 1 or 2 (ABL1, ABL2), platelet-derived growth factor receptor, and SRC (proto-oncogene encoding a non-receptor tyrosine kinase, similar to the v-Src gene of the Rous sarcoma virus), could potentially provide benefit for SARS-CoV-, MERS-CoV-, or SARS-CoV-2-infected patients (77). For instance, the ABL inhibitor, ponatinib, exhibited cytokine storm suppression in a preclinical model of influenza (78). Imatinib inhibited TNF-alpha production in murine models of acute hepatitis and prevented TNF-alpha-dependent acute liver inflammation in these models (77), and attenuated signaling associated with rheumatoid arthritis, such as KIT-mediated signaling and TNF-alpha release by mast cells, macrophage FMS activation and production of cytokines (79). Nilotinib and bosutinib showed activity against pulmonary fibrosis and other models of fibrosis, through regulation of levels of pro-inflammatory cytokines such as IL-1 and IL-6 (80) (81) (82) (83) (84) (85) (86) (87) (88) (89).\nCase study reports and small clinical trial data exist, generally in favor of the anti-inflammatory and antifibrotic effects of imatinib, although results have been variable. Two targets of imatinib are ABL, which is a key downstream mediator of profibrotic TGF-beta signaling, and PDGFR, also associated with fibrotic diseases (90). In chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST) patients, imatinib treatment improved rheumatoid arthritis symptoms, suggesting anti-inflammatory activity, and downregulated proinflammatory cytokines, IL-6 and IL-8 (91) (92) (93). Antifibrotic effects of imatinib were demonstrated in two patients with nephrogenic systemic fibrosis, with each patient showing progressive reduction of skin thickening and tethering following the start of imatinib treatment (94), and pulmonary fibrosis improved in a patient treated with imatinib for the 20 weeks the patient was on therapy (95). Antifibrotic activity of imatinib was also demonstrated in a patient with bleomycin interstitial pneumonitis, a condition sharing biochemical and histological features with idiopathic pulmonary fibrosis that is caused by the antibiotic chemotherapy agent bleomycin (96). However, imatinib was not observed to affect lung function or survival in idiopathic pulmonary fibrosis patients followed for 96 weeks in a randomized, placebo-controlled clinical trial (97), and limited success was observed for imatinib in a Hodgkin’s lymphoma patient with bleomycin interstitial pneumonitis due to adverse effects including thrombocytopenia with gastrointestinal bleeding (98).\nSRC kinases are activated by profibrotic cytokines TGF-beta and PDGF (99), and SRC kinases are important for inflammatory responses (100). Dasatinib has been proposed as an agent for fibrotic diseases, based on its inhibition of TGFbeta-induced myofibroblast differentiation through SRC-mediated signaling in vitro (101). Dasatinib blocked production of pro-inflammatory cytokines in a model of autoimmune arthritis, including IL-1, TNF-alpha, and IL-6, and stimulated production of the anti-inflammatory cytokine IL-10 (102) (103), and caused macrophages to change to an anti-inflammatory phenotype marked by high IL-10 production and suppression of levels of pro-inflammatory cytokines (IL-6, TNF-alpha) (104). Preclinical studies with the SRC/ABL inhibitor, saracatinib, which has orphan drug status for idiopathic pulmonary fibrosis, showed that it decreases collagen deposition and fibroblast activity, which are characteristic of lung fibrosis (105). Specifically, saracatinib, in an in vitro lung fibroblast model, inhibited TGF-beta-induced SRC activation and consequently inhibited myofibroblast differentiation, supporting the notion that SRC promotes myofibroblast differentiation and lung fibroblast activation (105). Saracatinib also showed efficacy in a mouse model of bleomycin-induced lung fibrosis 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