It is remarkable that a pathway as ubiquitous as protein quality control can be targeted to treat cancer. Bortezomib, an inhibitor of the proteasome, was first approved by the US Food and Drug Administration (FDA) more than 10 years ago to treat refractory myeloma and later extended to lymphoma. Its use has increased the survival rate of myeloma patients by as much as three years. This success was followed with the recent accelerated approval of the natural product derived proteasome inhibitor carfilzomib (Kyprolis^®), which is used to treat patients with bortezomib-resistant multiple myeloma. The success of these two drugs has validated protein quality control as a viable target to fight select cancers, but begs the question why are proteasome inhibitors limited to lymphoma and myeloma? More recently, these limitations have encouraged the search for additional targets within the protein quality control system that might offer heightened cancer cell specificity, enhanced clinical utility, a lower rate of resistance, reduced toxicity, and mitigated side effects. One promising target is p97, an ATPase associated with various cellular activities (AAA+) chaperone. p97 figures prominently in protein quality control as well as serving a variety of other cellular functions associated with cancer. More than a decade ago, it was determined that up-regulation of p97 in many forms of cancer correlates with a poor clinical outcome. Since these initial discoveries, a mechanistic explanation for this observation has been partially illuminated, but details are lacking. Understandably, given this clinical correlation, myriad roles within the cell, and its importance in protein quality control, p97 has emerged as a potential therapeutic target. This review provides an overview of efforts towards the discovery of small molecule inhibitors of p97, offering a synopsis of efforts that parallel the excellent reviews that currently exist on p97 structure, function, and physiology.

This review examines the extent to which natural systems have adopted the Paal–Knorr reaction to engage nucleophilic amine groups within biological targets.

Significance: The advance of new clinical treatment options for cancer relies heavily on the discovery of chemotherapeutic agents with new modes of action. In this paper, we describe the discovery of a potent melanoma-selective agent, seriniquinone, and elucidate its targeting of dermcidin and dermcidin-conjugated proteins within tumor cells. Early evidence indicates a direct correlation between seriniquinone activity and the levels of dermcidin within an ascribed tumor cell line, therein suggesting not only a unique target and avenue for further therapeutic exploration but also, and perhaps more importantly, revealing that dermcidin that may play a dual role as a diagnostic patient preselection biomarker and a drug target.