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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.
Diversity Analysis of Indian Mangrove Organisms to Explore Their Potential in Novel and Value-Added Biomolecules
Published in Jayanta Kumar Patra, Gitishree Das, Sanjeet Kumar, Hrudayanath Thatoi, Ethnopharmacology and Biodiversity of Medicinal Plants, 2019
Angana Sarkar, Sushant Prajapati, Amulya Sai Bakshi, Asma Khatoon, Raghavarapu Swathi, Siddharth Kumar, Arpita Behera, Rahul Pradhan
The proof of the massive potential of MNPs is shown by the growth of mangrove organism derived drugs. Many useful drugs, particularly in the field of cancer chemotherapy can be developed from the mangrove which offers a rich source of biodiversity. Currently, seven FDA or EMA approved drugs from marine sources, most of which are antitumor drugs, are potentially increasing in the market. About 20 are presently in clinical trials Phase I, I/II, II or III and a very promising candidate is salinosporamide A (marizomib) which is an active β-lactone produced by actinomycete Salinispora tropica. It is an inhibitor of the 20S proteasome and is currently in clinical development for the treatment of hematological malignancies (mainly of multiple myeloma). Although cancer is the main indication, an extension of the range of indications can also be expected, for example, a candidate against Alzheimer disease which targets nicotinic acetylcholine receptors is in Phase II (DMXBA). The global mangrove pharmaceutical pipeline includes eight Food and Drug Administration (FDA) or European Medicines Agency (EMEA) approved drugs and several compounds in different phases of the clinical pipeline. The market is continuously blooming for mangrove nutraceuticals and cosmetics.
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].