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Review
. 2022 Nov 15;2(12):2636-2644.
doi: 10.1021/jacsau.2c00448. eCollection 2022 Dec 26.

40 Years of Duocarmycins: A Graphical Structure/Function Review of Their Chemical Evolution, from SAR to Prodrugs and ADCs

Jan G Felber  1 , Oliver Thorn-Seshold  1
Affiliations
Review

40 Years of Duocarmycins: A Graphical Structure/Function Review of Their Chemical Evolution, from SAR to Prodrugs and ADCs

Jan G Felber et al. JACS Au. .

Erratum in

Abstract

Synthetic analogues of the DNA-alkylating cytotoxins of the duocarmycin class have been extensively investigated in the past 40 years, driven by their high potency, their unusual mechanism of bioactivity, and the beautiful modularity of their structure-activity relationship (SAR). This Perspective analyzes how the molecular designs of synthetic duocarmycins have evolved: from (1) early SAR studies, through to modern applications for directed cancer therapy as (2) prodrugs and (3) antibody-drug conjugates in late-stage clinical development. Analyzing 583 primary research articles and patents from 1978 to 2022, we distill out a searchable A0-format "Minard map" poster of ca. 200 key structure/function-tuning steps tracing chemical developments across these three key areas. This structure-based overview showcases the ingenious approaches to tune and target bioactivity, that continue to drive development of the elegant and powerful duocarmycin platform.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a) 583 duocarmycin research reports were classified by a nine-point scheme, then structurally analyzed. (b) The A0-sized Poster S1 “Minard map” summarizes the structural evolution of >200 duocarmycin-derived agents from SAR to prodrugs and ADC.
Figure 2
Figure 2
Literature metrics. (a) 583 primary research items form the duocarmycin literature database reviewed here. Charts show the major research groups (>20 publications) and journals (>10 publications). (b) The literature was grouped as: (a) natural products, biochemistry, and molecular mechanism of CC-1065 and close analogues; (b) initial clinical trial compounds; then the focus groups of this Perspective: (1) synthetic analogues and SAR; (2) prodrugs and bifunctional conjugates; (3) ADCs. Group histograms reveal the chronological progress of duocarmycin research. Paper/patent ratios may indicate perceived commercialisation chances.
Figure 3
Figure 3
Structural developments of the duocarmycins (cartoon; all chemical structures in Poster S1). In Group 1 (SAR compounds), studies resolved the molecular motifs crucial for rational tuning of bioactivity. In Group 2 (Prodrugs), non-natural prodrugs (glycosides, nitroaryls, carbamates, N-oxides) and bifunctional conjugates expanded the scope of duocarmycins. In Group 3 (ADCs), industry has been a main driver of research.
Figure 4
Figure 4
Structural elements of duocarmycin therapeutics. (a) SAR analysis: variations of segments A and B. (b) Activatable prodrugs: strategies to trigger bioactivity. (c) Antibody–drug conjugates: CBI-ADCs including clinical candidates SYD985 and MDX-1302. See also Poster S1.
Figure 5
Figure 5
Color-coded highlights of the disruptive chemical steps that have led the duocarmycins from isolation to the clinic (see also Poster S1). (Key: A,B = A-,B-segments. C = intracellular cleavage site. S = solubilizer. L = self-immolative spacer. R = reactive group for antibody conjugation.)
See this image and copyright information in PMC

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