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Therapeutic Use of Carbonic Anhydrase Inhibitors and Their Multiple Drug Interactions
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Andrea Angeli, Claudiu T. Supuran
Indisulam (E7070) is another small molecule as anticancer agent that is currently being evaluated in phase II clinical studies (Haddad et al., 2004). The precise mechanism of action has not been determined, since it showed multiple mechanisms of action such as inhibitor of hCA IX and XII (Supuran, 2003) and multiple cell-cycle checkpoints (Ozawa et al., 2012) Also for this compound there are few reports regarding the interactions of these agents with other drugs. A phase I clinical trial reported the excessive hematological toxicity with relatively high exposure to carboplatin (Dittrich et al., 2007). In addition, the plasma protein binding of acenocoumarol was reduced at higher concentrations of E7070. This is caused by potential inhibition of cytochrome CYP2C9 that is the major enzyme involved in the metabolism of acenocoumarol. This could be lead to hypoprothrombinemia (van den Bongard et al., 2004).
Novel approaches to targeted protein degradation technologies in drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Yu Xue, Andrew A. Bolinger, Jia Zhou
Another type of MG besides IMiDs-based MGs is aryl-sulfonamides, exemplified by indisulam (17). Indisulam has been reported to show potent anticancer activity against several hematological tumors, but the MoA and primary targets of indisulam have remained unclear [31]. In 2017, the research groups of Nijhawan’s and Owa’s first and independently reported the role of indisulam as MG in inducing RNA binding motif protein 39 (RBM39) and coactivator of activating protein-1 and estrogen receptor α (CAPERα) degradation [32,33]. A further retrospective study demonstrated that indisulam hijack E3 ligase DDB1 and CUL4 associated factor 15 (DCAF15) to degrade RBM39 and RBM23 [34]. The indisulam was found to function as an MG to facilitate the formation of a new surface of DCAF15 to recruit RBM39, rather than allosterically modulating them, nor by stabilizing weak DCAF15-RBM interactions. The conserved sulfonamide moiety provides the key interactions [35]. Specifically, the central sulfonyl oxygens form interactions with backbone amide from DCAF15 residues, while the nitrogen forms water-mediated H-bonds with RBM39 side chains. Notably, aryl-sulfonamides showed weaker affinity (>50 μM) when binding to DCAF15 compared with IMiDs (100 ~ 200 nM), but this deficiency was compensated by the nearly doubling of the interfacial surface area between DCAF15 and RBM39. Three analogs with the same central sulfonamide, tasisulam (18), E7820 (19), and chloroquinoxaline sulfonamide (CQS, 20), were also reported as MGs to induce RBM23/39 degradation via the DCAF15-dependent pathway [32,33,36].
Experimental drugs in clinical trials for acute myeloid leukemia: innovations, trends, and opportunities
Published in Expert Opinion on Investigational Drugs, 2023
Aleksandra Gołos, Joanna Góra-Tybor, Tadeusz Robak
RBM39 is an RNA-binding protein essential for cancer cell survival [77]. Its proteasomal degradation by indisulam or tasisulam, sulfonamide derivates, results in the downregulation of checkpoint molecules [77]. The efficacy of indisulam (E7070) in combination with idarubicin and cytarabine was examined in a phase 2 clinical trial in patients with RR AML and RR high-risk MDS [78]. The study enrolled 40 patients with a median age of 63 years (range: 25–75) and a median number of treatment lines of 2 (1–6). The ORR was 35%, including 26% of CR. The median time of response duration was 5 months. After a median follow-up of 6 months, the OS was 5,2 months (range, 0,6–40; 95% confidence interval [CI] 4,96–10,21) and was significantly longer for responders than for non-responders (17,4 vs. 4,3, months; hazard ratio [HR] 0.32, 95% CI [0,18–0,67] p = 0.004) [78]. The most common grade 3/4 toxicities were electrolyte abnormalities (50%), febrile neutropenia (28%), pneumonia (18%), and diarrhea (10%) [78]. A newer sulfonamide derivate, E7820, is currently being investigated in a phase 2 clinical study in patients with RR AML, MDS, and CMML with mutations in splicing factors (NCT05024994).
Biomedical applications of prokaryotic carbonic anhydrases
Published in Expert Opinion on Therapeutic Patents, 2018
Claudiu T. Supuran, Clemente Capasso
Derivatives 1–24 and AAZ-HCT are either simple aromatic/heterocyclic sulfonamides widely used as building blocks for obtaining new families of such pharmacological agents, or they are clinically used agents, among which acetazolamide (AAZ), methazolamide (MZA), ethoxzolamide (EZA), and dichlorophenamide (DCP) are the classical, systemically acting antiglaucoma CAIs. Dorzolamide (DZA) and brinzolamide (BRZ) are topically acting antiglaucoma agents; benzolamide (BZA) is an orphan drug belonging to this class of pharmacological agents. Moreover, the zonisamide (ZNS), sulthiame (SLT), and the sulfamic acid ester topiramate (TPM) are widely used antiepileptic drugs. Sulpiride (SLP) and indisulam (IND) were also shown by our group to belong to this class of pharmacological agents, together with the COX2 selective inhibitors celecoxib (CLX) and valdecoxib (VLX). Saccharin (SAC) and the diuretic hydrochlorothiazide (HCT) are also known to act as CAIs. Sulfonamides, such as the clinically used derivatives AAZ, MZA, EZA, DCP, DZA, and BRZ, bind in a tetrahedral geometry to the Zn(II) ion in the deprotonated state, with the nitrogen atom of the sulfonamide moiety coordinated to Zn(II) and an extended network of hydrogen bonds, involving amino acid residues of the enzyme, also participating in the anchoring of the inhibitor molecule to the metal ion [45–47,62]. The aromatic/heterocyclic part of the inhibitor interacts with the hydrophilic and hydrophobic residues of the catalytic cavity [46–49].