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Other Novel Targeted Therapies in Lung Cancer
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
Kyriakos P. Papadopoulos, Anthony W. Tolcher
PR-171 is an epoxomicin-derived second-generation proteasome inhibitor that selectively and irreversibly inhibits the proteasome (157). Proteasome activity appears to recover rapidly in normal tissue. Antitumor activity has been demonstrated in a number of xenograft mouse models, and a phase-I clinical trial is currently underway in hematologic malignancies.
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Carfilzomib (KyprolisTM) is a selective proteasome inhibitor developed by Onyx Pharmaceuticals (Figure 6.84). It is a tetrapeptide epoxyketone analog of the natural product epoxomicin that was known to disrupt tumor cell turnover and induce apoptosis. Epoxomicin was shown by Craig Crews and co-workers at Yale University to inhibit the proteasome, and they went on to design a more specific analogue (YU101), which was subsequently licensed to Proteolix Inc. This company produced an analogue (later to be named carfilzomib) which was advanced to Phase 1 and 2 clinical trials, including a pivotal Phase 2 clinical trial designed to seek accelerated approval. Proteolix was acquired by Onyx Pharmaceuticals in 2009, and in 2011 the FDA granted fast track status. Carfilzomib gained FDA approval in 2012 for the treatment of multiple myeloma in patients who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy (such as lenalidomide), and have disease progression on or within 60 days of completion of the last therapy. In the UK it is recommended by NICE to be used in combination with dexamethasone, or with dexamethasone and lenalidomide, for the treatment of multiple myeloma in patients who have received at least one prior therapy. Structure of carfilzomib (KyprolisTM).
Chemical tools to monitor bladder cancer progression
Published in Biomarkers, 2022
Natalia Gruba, Lech Stachurski, Adam Lesner
Next, we decided to screen mixed urine samples with inhibitors of certain classes of proteolytic enzymes (Table 4). Such an experiment allowed us to pre-determinate which class of enzymes is responsible for the observed activity. The result of this experiment is shown in Figure 4. Incubation of G1 urine with leupeptin resulted in a decrease in the hydrolysis efficiency, which could suggest the presence of serine or cysteine proteinases. The proteolytic activity was also reduced to some extent after the use of carfilzomib and epoxomicin which are proteasome inhibitors. Such a result could suggest the presence of threonine proteinases. Similar situation was observed in G2 urine. Proteolytic activity was inhibited by about 50% after the use of leupeptin and to some extent after incubation with PMSF. The situation is different in the case of G3 mixed urine. Here, we observed a 60% decrease in activity after incubation with AHX-VYDnVP (C6H2Cl)2 described as the most potent peptidyl irreversible inactivators of neutrophil elastase (HNE) (33). The use of inhibitors of different classes of enzymes did not result in a decrease in the hydrolysis efficiency. The results obtained for each stage of cancer development are not unequivocal. On the one hand, we observed a certain decrease in activity after the use of inhibitors of various classes of enzyme, on the other hand, we did not observe complete enzyme inhibition in any case. Such a result may suggest that the activity we are monitoring correlates with a different type of enzyme than we used.
Approaches to mitigate the risk of serious adverse reactions in covalent drug design
Published in Expert Opinion on Drug Discovery, 2021
Finally, it should be pointed out that many natural products contain electrophilic functional groups and have served as templates for the design of highly selective TCIs [50]. A prominent example here is the anti-cancer drug carfilzomib (Kypolis), a derivative of the linear peptide epoxyketone epoxomicin that serves as a covalent inhibitor of the 20S proteosome. Mechanism of action studies with epoxomicin revealed that its high selectivity toward the proteosome relative to other protease enzymes derives from the unexpected formation of a 6-membered morpholino ring between the terminal catalytic Thr-1 residue of the proteosome and the α’, α’-epoxyketone pharmacophore of epoxomicin [51] (Figure 3). Carfilzomib, a more water-soluble analog of the corresponding natural product, retains this mechanism of action and the high selectivity of epoxomicin, and was approved for use in 2012 for the treatment of multiple myeloma.
Regulation of cytochrome P450 enzyme activity and expression by nitric oxide in the context of inflammatory disease
Published in Drug Metabolism Reviews, 2020
Edward T. Morgan, Cene Skubic, Choon-myung Lee, Kaja Blagotinšek Cokan, Damjana Rozman
Interpretation of the calpain inhibitor results is complicated by our finding that the CYP2J2, CYP2B6 and CYP2A6 -specific enzyme inhibitors danazol, 4-chlorophenylimidazole and pilocarpine respectively blocked NO-dependent degradation of these enzymes (Park et al. 2018; Cerrone Jr et al. 2020; Lee et al. 2020). In the context of protease inhibition, this signifies that protease inhibitors should be tested for their ability to directly inhibit the P450 enzyme under study. Indeed, the prototypic proteasome inhibitors MG132 and epoxomicin inhibit CYP3A4 in cultured human hepatocytes, whereas the therapeutic proteasome inhibitor bortezomib does not (Lee et al. 2010). We found that Cal III, but not calpeptin inhibited catalytic activity of CYP2J2. Thus the inhibition of CYP2J2 degradation by calpeptin may be indeed be due to calpain inhibition. However, we also found that CYP2J2 degradation was not inhibited by the calcium chelator BAPTA-AM as would be expected for a calcium-dependent protease (Park et al. 2018). Therefore the involvement of calpains in CYP2J2 degradation remains to be conclusively established. In the absence of a facile assay for CYP51A1 (which routinely entails 3H labeled substrates in a reconstituted enzyme system (Cotman et al. 2004)) we do not know what effect calpain or proteasome inhibitors might have on its activity.