Preclinical Development of Seriniquinones as Selective Dermcidin Modulators for the Treatment of Melanoma

Abstract

The bioactive natural product seriniquinone was discovered as a potential melanoma drug, which was produced by the as-yet-undescribed marine bacterium of the rare genus Serinicoccus. As part of a long-term research program aimed at the discovery of new agents for the treatment of cancer, seriniquinone revealed remarkable in vitro activity against a diversity of cancer cell lines in the US National Cancer Institute 60-cell line screening. Target deconvolution studies defined the seriniquinones as a new class of melanoma-selective agents that act in part by targeting dermcidin (DCD). The targeted DCD peptide has been recently examined and defined as a "pro-survival peptide" in cancer cells. While DCD was first isolated from human skin and thought to be only an antimicrobial peptide, currently DCD has been also identified as a peptide associated with the survival of cancer cells, through what is believed to be a disulfide-based conjugation with proteins that would normally induce apoptosis. However, the significantly enhanced potency of seriniquinone was of particular interest against the melanoma cell lines assessed in the NCI 60-cell line panel. This observed selectivity provided a driving force that resulted in a multidimensional program for the discovery of a usable drug with a new anticancer target and, therefore, a novel mode of action. Here, we provided an overview of the discovery and development efforts to date.

Keywords: apoptosis; autophagy; dermcidin; marine natural products; melanoma; seriniquinone.

Figure 1

Aerial view of the Rock Islands of Palau where Serinicoccus was discovered (left) and the Gram-positive bacterium Serinicoccus sp. growing on a seawater-based nutrient agar surface (right).

Figure 2

Crystals of seriniquinone as isolated and the chemical structure assigned (left), as well as activity data on seriniquinone (right). Bioassay results for seriniquinone against the 60-cell line panel offered by the Developmental Therapeutics Program at the NCI. Melanoma cell lines are highlighted in orange. A few other cell lines were also more sensitive to seriniquinone.

Figure 3

Synthetic approach to the seriniquinones. To date, a central synthetic approach has been established that enabled analogue preparation at four positions within each of the two ring systems. Seriniquinone (shown in Figure 2) is represented by R^1a−4a = H and R1^b−4b = H.

Figure 4

Exemplary analogues of seriniquinone prepared to date. IC₅₀ values are provided for each compound against Malme-3M cells. Under these conditions, the parent seriniquinone (R^1a–R^4a = H and R^1b–R^4b = H) displayed an IC₅₀ value of 60 nM.

Figure 5

Current structure–activity relationship (SAR) maps obtained from mono- and di-substituted analogues. Undesired (red) depict modifications whose activity was significantly less than seriniquinone (R^1a–R^4a = H and R^1b–R^4b = H) (<50 nM in Malme-3M cells). Tolerated (green) denote analogues whose activity was similar to that of seriniquinone (R^1a–R^4a = H and R^1b–R^4b = H) (i.e., 60 ± 10 nM in Malme-3M cells). Undesired modifications that led to a reduction in activity are shown in red circles (≥100 nM in Malme-3M cells). An unfilled blue circle depicts unexplored sites.

Figure 6

Timeline of melanoma therapy showing the mainly used drugs, along with the mean overall survival archived by patients and the total cost of the treatment per patient [16,17,18,19,20,21,22,23].

Figure 7

Multiple roles of dermcidin in cancer cells. In addition to the well-described role in skin defense with antimicrobial peptides, dermcidin (DCD) may be involved in a few processes of many types of cancer cells, as illustrated. Proteolysis-inducing factor (PIF), another DCD derivative, is related to cachexia in cancer.