Searching for an ideal SERM: Mining tamoxifen structure-activity relationships.

The repurposing of old drugs for new treatments has recently garnered increased attention in the face of new diseases and declining productivity of the pharmaceutial industry. This report draws attention to potential opportunities hiding in plain sight within the SAR of off-patent drugs. Herein we explore the untapped potential of Selective Estrogen Receptor Modulators (SERMs). SERMs are a class of molecules that have been highly influential in the treatment of estrogen receptor-positive breast cancers. However, the most commonly prescribed SERM, tamoxifen, has been found to increase the risk of endometrial cancer. Another SERM, raloxifene, does not increase incidence of endometrial cancer, but has been abandoned as a breast cancer treatment. We report the design, synthesis, and evaluation of an unexplored tamoxifen substitution pattern which mimics the geometry of raloxifene to confer its favorable pharmacodynamics. This substitution pattern was found to maintain excellent binding affinity to estrogen receptor-α.

Probing metalloenzyme dynamics in living systems: Contemporary advances in fluorescence imaging tools and applications.

Metalloenzymes are essential to cellular function, and their overexpression or enhanced activation are potential therapeutic targets. However, the study of metalloenzymes in vitro presents various challenges, leading many to develop tools to study them in their native cellular environment. Small-molecule fluorescence probes are commonly used to monitor metalloenzyme function, activity, and distribution in situ. These include probes that are activity-based (fluorescence is mediated by enzyme activity) or binding-based (fluorescence is mediated by interactions with the enzyme upon binding its metal cofactor). We discuss recent innovations that overcome key design challenges, such as the rapid diffusion of activity-based probes, the difficulty of probing redox-active enzymes, the selectivity of binding-based probes, and the poor penetration depth of fluorescence, and describe novel applications of these tools.

Structural insights into the design of reversible fluorescent probes for metallo-ß-lactamases NDM-1, VIM-2, and IMP-1.

Metallo-ß-lactamases (MBLs) are enzymes that are capable of hydrolyzing most ß-lactam antibiotics and all clinically relevant carbapenems. We developed a library of reversible fluorescent turn-on probes that are designed to directly bind to the dizinc active site of these enzymes and can be used to study their dynamic metalation state and enzyme-inhibitor interactions. Structure-function relationships with regards to inhibitory strength and fluorescence turn-on response were evaluated for three representative MBLs.