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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
BatimastatTM (Figure 6.108) was the first MMP inhibitor to enter Phase I clinical trials in the early 1990s. It reached Phase III but was not marketed as it could not be administered orally (as opposed to the chemically similar MarimastatTM), and the preferred dosing route of injection into the peritoneum caused peritonitis.
Antiangiogenic Therapy for Lung Cancer: Small-Molecule Inhibitors
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
These may be direct inhibitors such as TNP-70, a synthetic analogue of fumagillin, a fungus-derived inhibitor of endothelial cell proliferation, the matrix metalloproteinase inhibitors (MMPIs) such as marimastat and batimastat, and Vitamin D3 (mechanism of antiangiogenesis unknown). “Indirect inhibitors” can be considered as those that inhibit angiogenic signaling, such as monoclonal antibodies directed against VEGF isoforms or small-molecule tyrosine kinase inhibitors (TKIs) directed at VEGFRs.
Bone morphogenetic protein signaling in breast cancer progression
Published in Growth Factors, 2019
Lap Hing Chi, Allan D. Burrows, Robin L. Anderson
The ability of cancer cells to invade the stroma is frequently measured by migration and invasion assays in vitro (Table 1). BMPs have been reported to regulate this process through various mechanisms. For instance, the level and activity of matrix metalloproteinases (MMPs) that promote tumor invasion and dissemination are regulated by BMP signaling. BMP2 upregulates the expression of MMP11 (Huang et al. 2017), while BMP4 stimulates the expression or activity of MMP1, MMP2 and MMP9, and promotes the invasion of cancer cells. This invasive phenotype is reversed by the MMP inhibitor Batimastat or the BMP antagonists Chrdl1, Noggin and Gremlin (Ampuja et al. 2013; Cyr-Depauw et al. 2016; Guo, Huang, and Gong 2012). Contrary to these reports, BMP4 downregulates the expression of MMP9 induced by PMA (a protein kinase C ligand) in MDA-MB-231, SKBR3 and the SMAD4-null MDA-MB-468 cells, although the mechanism is unclear (Laulan and St-Pierre 2015). Also, BMP6 downregulates MMP1 and MMP9, potentially through canonical signaling that mediates the suppression of p38/AP-1, and inhibits invasion (Hu et al. 2016; C. Wang et al. 2011). BMP9 overexpression leads to reduced production of MMP9, where a concomitant reduction of p-AKT is observed (S. Li et al. 2018).
Metalloproteinases in disease: identification of biomarkers of tissue damage through proteomics
Published in Expert Review of Proteomics, 2018
Cristina Herrera, Teresa Escalante, Alexandra Rucavado, Jay W. Fox, José María Gutiérrez
Local hemorrhage is one of the most prominent manifestations of envenomings by viperid snakes [78]. Ultrastructural observations demonstrated that this effect occurs predominantly in capillary vessels, with drastic alterations observed in endothelial cells and the surrounding BM [79]. In vitro experiments indicate that SVMPs hydrolyze the main components of the BM, that is, laminin, type IV collagen, nidogen, and BM-specific heparan sulphate proteoglycan (perlecan) [58,80–82]. Moreover, histochemistry, immunohistochemistry, and Western blot analyses further demonstrated the hydrolysis and loss of these components in vivo [58,60,72,81,83]. Proteomic analysis corroborated these observations, since fragments of BM proteins were detected in exudates as a consequence of proteolysis [55,58,60,72,84]. The role of SVMPs in this effect was demonstrated by using the metalloproteinase inhibitor Batimastat, which abrogates the pathology [84]. The fact that BM protein fragments were detected in samples collected as early as 15 min after SVMP injection strongly suggests a direct hydrolysis of BM components by venom enzymes. Moreover, proteomic analysis demonstrates that the proteins detected mostly correspond to cleaved fragments.
Recent opportunities in matrix metalloproteinase inhibitor drug design for cancer
Published in Expert Opinion on Drug Discovery, 2018
Yue Zhong, Yu-Ting Lu, Ying Sun, Zhi-Hao Shi, Nian-Guang Li, Yu-Ping Tang, Jin-Ao Duan
Over the past 30 years, MMPs have been considered as attractive cancer targets and many different types of synthetic inhibitors have been identified as anticancer drugs [84]. However, only a small number of MMPIs have undergone clinical trials, and several trials were prematurely terminated due to either the lack of benefits or major adverse effects and failed to reach their expectations of increasing survival [85]. For example, Batimastat was the first MMPI entered into clinical trials for the treatment of cancer [86]. In phase I studies, Batimastat was administered to patients with malignant ascites, as well as malignant pleural effusion via direct instillation into the peritoneal and pleural cavities. Batimastat was well tolerated, but short-lasting mild abdominal pain associated with nausea and vomiting was noted in approximately half of the patients; thus, further development of this compound has been suspended. Marimastat, another MMPI, was demonstrated as efficient in phase III trials toward pancreas cancer but failed in breast or lung cancer. Severe musculoskeletal pain was noted in 18% of patients treated with Marimastat, and the quality of life was significantly worse in this group of patients [87].