The “Utility” of Highly Toxic Marine-Sourced Compounds

Abstract

Currently a few compounds isolated from marine sources have become drugs, mainly directed towards cancer and pain. Compounds from marine sources have exquisite potencies against eukaryotic cells, as they act as protective agents against attack by predators in the marine environment. Their toxicities act as a “double-edged sword” as they are often too toxic for direct use in humans and thus have to be chemically modified. By linking suitably modified compounds to monoclonal antibodies directed against specific epitopes in mammalian cancer cells, they can be delivered to a specific cell type in humans. This review updates and extends an article published in early 2017, demonstrating how by careful chemical modifications, highly toxic compounds, frequently peptidic in nature, can be utilized as antitumor drug candidates. The antibody-drug- conjugates (ADCs) discussed are those that are currently in clinical trials listed in the NIH Clinical Trials Registry as, “currently active, recruiting or in some cases, recently completed”. There are also some ADCs discussed that are at the advanced preclinical stage, that in some cases, are repurposing current drug entities, and the review finishes with a short discussion of the aplyronines as potential candidate warheads as a result of scalable synthetic processes.

Site-selective modification strategies in antibody–drug conjugates

“…32 A wealth of knowledge now exists on the specific requirements for the three individual ADC components; the antibody, the cytotoxic drug and the linker. Whilst the natures of the target antigen, antibody, 1,28,33 linker-drug attachment 16,26 and payload [34][35][36] are all crucial to the pharmacology of an ADC, this review will focus on the developments in conjugation technology.…”

“…9A). 36,125 The ADC has recently received FDA orphan drug designation for the treatment of pancreatic and gastric cancer based on promising preclinical data. OBI is currently recruiting patients with locally advanced or metastatic solid tumours, including gastric, pancreatic, oesophageal and colorectal cancers, for a Phase I/II study (ClinicalTrials.gov Identifier: NCT04084366).…”

“…This ADC has demonstrated promising tumour growth inhibition or regression in patient-derived xenograft models in mice, including models with KRAS/BRAF mutations typically associated with resistance to EGFR-targeted therapy and poor outcome. 36,126 Furthermore, HTI-1511 has been shown to be well tolerated in primate models.…”

Marine Anticancer Agents: An Overview with a Particular Focus on Their Chemical Classes

“…To exploit the potent antimitotic effect and improve the pharmacokinetic profile, structural modifications of dolastatin 10 have been developed, resulting in the successful class of auristatins, which present differences in the C-terminus, from dolaphenine (Doe) in dolastatin 10 to phenylalanine in monomethyl auristatin-F (Phe). More importantly, auristatins appeared as great payloads in antibody-drug conjugates (ADCs) [132]. The efficacy of ADCs to exploit antibodies to target specific molecules on tumor cells and selectively deliver otherwise highly toxic molecules [133] is evident by the fact that four compounds belonging to this class have recently been approved for the treatment of patients with cancer (Table 1) and over 20 other compounds are in clinical evaluation [134][135][136].…”

Metabolites from marine invertebrates and their symbiotic microorganisms: molecular diversity discovery, mining, and application

“…Hence, MNPs are considered as an excellent and potentially valuable source for new chemical entities with novel structures and distinct mechanisms of action. To date, there have been 13 approved therapeutic agents that could be considered derivatives of MNPs (Altmann 2017;Jiménez 2018;Newman 2019;Pereira et al 2019). Moreover, more than 30 MNP derivatives constitute the global marine pharmaceutical clinical pipeline in Phases III, II or I of drug development (According to the following websites: http:// marin ephar macol ogy.midwe stern .edu; http://pharm a.id.infor ma.com (accessed on August 6, 2019); Jiménez 2018; Newman 2019; Pereira et al 2019).…”