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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Salinosporamide A has been evaluated in a wide range of preclinical studies, including in vivo models of both hematological (e.g., non-Hodgkin’s Lymphoma, Waldenstrom’s macroglobulinemia, acute lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, and chronic lymphoid leukemia) and solid (e.g., colon and pancreatic) cancers. Single-agent activity was observed in most of these models, along with synergistic effects when combined with other chemotherapeutic agents and some biologic therapies. At the time of writing, salinosporamide A is still being evaluated in clinical trials, including one study in glioblastoma as a first-line, combination or adjuvant therapy.
Methods in marine natural product drug discovery: what’s new?
Published in Expert Opinion on Drug Discovery, 2023
Jehad Almaliti, William H. Gerwick
Synthetic biology approaches have been recently applied to structure modifications and analog generation. Noteworthy examples include reprogramming of polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) modular enzymes, although these approaches usually suffer from low yields. Alternatively, characterization of enzymes involved in NP biosynthetic transformations is allowing their use as synthetic reagents of exceptional utility. For example, the γ-lactam-β-lactone bicyclic core of the proteasome inhibitor salinosporamide A is formed by a single standalone ketosynthase (KS), SalC, and represents a major step toward harnessing the activity of this enzyme for the efficient production of new-to-nature bioactive salinosporamides [14]. The Abe group has demonstrated a useful strategy for engineering NRPS-PKS module enzymes, based on nature’s diversification of the domain and module organization. As a result, they have accomplished ring contractions, ring expansions, and alkyl chain diversification of a family of cyclic depsipeptides (5) [15].
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].