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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Salinosporamide A, also known Marizomib, was developed by Nereus Pharmaceuticals as a potent proteasome inhibitor for the treatment of multiple myeloma (Figure 6.86). It is a novel marine natural product produced by the obligate marine bacteria Salinispora tropica and Salinispora arenico which are found in ocean sediment. The molecule has a densely functionalized γ-lactam-β-lactone bicycle core structure. It entered Phase I clinical trials only three years after its discovery in 2003. Structure of salinosporamide A.
Have marine natural product drug discovery efforts been productive and how can we improve their efficiency?
Published in Expert Opinion on Drug Discovery, 2019
In spite of marine invertebrates such as sponge, jellyfish, anemone, and a rocky coral have been the source of most bioactive MNPs, with Porifera (sponges) and Cnidaria phyla being the most prolific, the true origin of most MNPs appears to be the microorganisms who live with them in a symbiotic relationship [6]. Almost all of the MNPs approved as drugs or currently in clinical trials come from bacterial and cyanobacterial biosynthetic sources, e.g. brentuximab vedotin (Figure 1, cyanobacteria Symploca sp.) and salinosporamide A (Figure 2, actinobacteria Salinispora tropica) [5]. The Ascomycota (Fungi) and Actinobacteria have been among the four most widely collected phyla during the last years, along with Porifera and Cnidaria [6]. Therefore, microbial-derived compounds will almost certainly dominate the MNP field in the coming years.
Proteasome inhibition for the treatment of glioblastoma
Published in Expert Opinion on Investigational Drugs, 2020
Patrick Roth, Warren P. Mason, Paul G. Richardson, Michael Weller
Marizomib, initially known as NPI-0052 or salinosporamide A, is produced by the marine bacteria Salinispora tropica and Salinispora arenicola. It was discovered by researchers from the Scripps Institution of Oceanography in La Jolla, CA [48]. The drug is an irreversible inhibitor in the beta-lactone class that binds to all catalytic moieties of the proteasome (specifically β1, β2, β5) with IC50 values in the low to mid nanomolar range [49]. Administration of marizomib to patients with advanced solid tumors and hematological malignancies led to a functional inhibition of all proteasome subunits in peripheral blood mononuclear cells, with the most pronounced effect on the chymotrypsin-like activity [50]. Similar to other proteasome inhibitors, marizomib displays strong anti-cancer activity in vitro and in preclinical tumor models. Exposure of leukemia cells to marizomib led to caspase 8 and reactive oxygen species (ROS)-dependent apoptosis [51]. Following clinical testing in patients with multiple myeloma and other hematological malignancies, marizomib has also been studied in the context of glioblastoma (see below). In contrast to other proteasome inhibitors, marizomib crosses the blood-brain barrier, making it an attractive therapeutic option for tumors in the CNS. In this context, marizomib was administered to patients with CNS involvement of multiple myeloma [52]. Therapeutic activity was observed, which which together with other previous observations formed the basis for its further assessment in CNS tumors [52]. The toxicity profile of marizomib differs from other proteasome inhibitors and includes fatigue, nausea, headache, gait disturbances as well as visual and auditory hallucinations, but the drug is otherwise generally well tolerated [53]. Adverse events associated with the CNS may be attributed to the ability of the drug to cross the blood-brain barrier and further strengthened the rationale for its evaluation in CNS disease [53].
Methods in marine natural product drug discovery: what’s new?
Published in Expert Opinion on Drug Discovery, 2023
Jehad Almaliti, William H. Gerwick
Many of the previous efforts in marine pharmaceutical discovery have focused on the large and readily apparent organisms, such as sponges, corals, tunicates and macroalgae. Investigation of marine microbes has been a more recent pursuit but has nevertheless been highly productive in the discovery of bioactive molecules, such as salinosporamide A (1) (Figure 2) [1]. Nevertheless, appreciation of unique niches in marine environments that are populated by specialized microorganisms is only just developing but is certain to be an even more productive pursuit. For example and based on ecological reasoning and principles, an obligate bacterial symbiont of the shipworm Teredinibacter turnerae has been found to produce antibiotic compounds (e.g.turnercyclamycin A, 2) with potential for treating resistant pathogens in humans such as Acinetobacter baumannii [2]. In general, many of the bioactive metabolites that have been isolated from large marine organisms such as sponges, tunicates and sea slugs are actually the products of microbial metabolism, be they symbiotic or consumed bacteria of various types [3,4]. Another new method for discovering what are normally cryptic bacterial metabolites involves the in-situ recovery of expressed and secreted NPs, an approach made possible in part due to advances in analytical and informatic technologies as discussed below. Environmental cues are believed to activate expression of NPs that are silent under typical culture conditions; therefore, recovery and characterization of metabolites produced in-situ complements traditional laboratory culture approaches, and gives new insights into the natural roles of marine microbial NPs. This has led to detection of several known marine bacterial metabolites, including staurosporine (3), as well as unknown molecular species, from HP20 resin bags shallowly buried in tropical marine sediments [5]. The above sampling methods are being combined with ever more sophisticated bioassays for NPs with utility to human health. For example, cytological screening of cancer cells using high content microscopy in combination with vital stains provides significant insights into mechanisms of action, even in primary screening of impure fractions [6]. Another frontier that has been largely avoided due to the complexity of the techniques involved is the exploration of marine life for their useful macromolecules. Examples include the antiviral cyanobacterial proteins such as cyanovirin and scytovirin, and glycoproteins such as the antiviral (e.g. SARS-CoV-2) lectin griffithsin from red algae [7].