ReviewPost screenHow can the potential of the duocarmycins be unlocked for cancer therapy?
Introduction
Duocarmycins are a family of DNA minor groove-binding compounds with exquisite cytotoxicity originally identified in Streptomyces [1]. Cyclopropapyrroloindole-based duocarmycins, such as (+)-duocarmycin SA (DSA, 1) and CC-1065 (2, Fig. 1a), comprise a DNA recognition motif (DNA-RM) and a pharmacophore responsible for alkylating DNA (Fig. 1a). In the AT-rich regions of the minor groove, the N3 position of adenine performs a nucleophilic attack on the least substituted carbon in the duocarmycin cyclopropane in a stereoelectronically dependant manner, forming DNA adducts [2]. Synthetic manipulation of the DNA alkylating subunit (variation in ‘A’, Figs 1c and 2) dramatically impacts the cellular potency in the pM–nM range, with most compounds forcing cells to undergo apoptosis [3] via direct S-phase inhibition and subsequent cell cycle arrest [4].
Seco-duocarmycins derived from common scaffolds, such as CI (3), DSA (4), CPI (5), and CBI (6), are precursor molecules (Fig. 1b) that contain a phenolic hydroxyl group that is responsible for initiating rearrangement of the pharmacophore to produce a cyclopropane-containing cytotoxin, via a process known as spirocyclisation (Fig. 1c). The natural duocarmycin products are produced in the enantiomerically S form at the chloromethane chiral centre. The chiral configuration of the duocarmycins has been demonstrated to influence both the sequence selectivity of DNA alkylation and the potency [5]. In regard to the latter, the S enantiomer is 100–1000-fold more potent than the R enantiomer in generating DNA damage, and synthetic approaches are typically aimed at producing the pure S form for this reason [6].
Despite their considerable potential as therapeutics, market approval for the clinical use of duocarmycins has not yet been granted. Clinical administration of adozelesin [7], bizelesin [8] and the two carbamate prodrugs carzelesin [9] and KW-2189 [10] (carbamate protection shown in Figure 11 and 12, respectively) has been associated with severe adverse effects and no therapeutic index, leading to all trials being discontinued. Despite this clinical failure, interest in these molecules has remained high and has led to a large body of work that has demonstrated fascinating insights in both biological and chemical explorations [6]. The inherent capacity of duocarmycins to evade traditional resistance mechanisms and retain exquisite potency in multidrug-resistant cells 11, 12, 13 still attracts considerable interest from both academia and industry to develop new approaches for this class of molecule, with a focus on expanding the therapeutic index for patient benefit. Accordingly, in this review, we outline and discuss the most promising drug discovery strategies over the past decade focussed on maximising the potential of these powerful compounds derived and inspired by nature.
Section snippets
Hypoxia-activated duocarmycin prodrugs
Solid tumours typically contain regions of high cell density and poor vascularisation leading to low oxygenation and hypoxia. These regions are often therapy resistant and house some of the most aggressive cancerous cells [14]. Although hypoxic fractions remain an obstacle to effective treatment, they also offer opportunities for the development of hypoxia-activated prodrugs (HAPs). Generally, HAPs are designed to exploit the presence of one or two-electron oxidoreductases, which can catalyse
Antibody–drug conjugates
ADCs have gained prominence over the past decade, with nine approved drugs and >100 in clinical trials. ADCs combine the excellent targeting properties of antibodies with the cell-killing power of conjugated payloads [45]. Currently, none of the clinically approved ADCs have a duocarmycin as payload. Investigations to this end are discussed further herein.
Small-molecule drug conjugate and peptide–drug conjugate
Small-molecule drug conjugates (SMDC) and peptide–drug conjugates (PDC) are attractive because they are smaller than ADCs and, therefore, are likely to confer superior tumour penetration. Both SMDCs and PDCs are designed to exploit the specificities of protein-targeting small molecules or peptides and the cytotoxicity of nonspecific chemotoxins by combining them with a cleavable linker [67].
Initial work published in 2014 demonstrated that duocarmycins could be viable payloads for SMDCs by
Future perspectives
Nature has undoubtedly produced intricate compound architectures that have fascinated and inspired drug hunters for medicinal use. Despite the promise of the powerful cell-killing duocarmycins, they have yet to be approved for clinical use. As reviewed here, several promising tumour-selective prodrug and ADC approaches are underway, with the latter strategy especially gaining momentum. For both prodrug and ADC strategies, low enzyme or antigen expression as well as tumour penetration are
Acknowledgements
The authors would like to thank Institute of Cancer Therapeutics Doctoral Training Centre for a PhD studentship to Z.J. and Yorkshire Cancer Research (Programme grant B381PA) for supporting our work focused on exploring CYPs as targets for duocarmycins bioprecursor development.
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