Unique chemical methodology enables the synthesis of innovative and diverse scaffolds and chemotypes and allows access to previously unexplored “chemical space.” Compound collections based on such new synthetic methods can provide small-molecule probes of proteins and/or pathways whose functions are not fully understood. We describe the identification, characterization, and evolution of two such probes. In one example, a pathway-based screen for DNA damage checkpoint inhibitors identified a compound, MARPIN (ATM and ATR pathway inhibitor) that sensitizes p53-deficient cells to DNA-damaging agents. Modification of the small molecule and generation of an immobilized probe were used to selectively bind putative protein target(s) responsible for the observed activity. The second example describes a focused library approach that relied on tandem multicomponent reaction methodologies to afford a series of modulators of the heat shock protein 70 (Hsp70) molecular chaperone. The synthesis of libraries based on the structure of MAL3-101 generated a collection of chemotypes, each modulating Hsp70 function, but exhibiting divergent pharmacological activities. For example, probes that compromise the replication of a disease-associated polyomavirus were identified. These projects highlight the importance of chemical methodology development as a source of small-molecule probes and as a drug discovery starting point.
Merkel cell carcinoma can be indolent: A case with 7 locoregional recurrences over 15 years highlights the importance of patient-tailored management
Patients who experience a recurrence of their Merkel cell carcinoma are often treated aggressively. We report a case of a man with an unusually long course of MCC over 15 years who had his MCC recur around his face or neck 7 times before eventually developing distant spread. Because he had 4 major medical problems at the time his MCC initially appeared, less aggressive therapies were chosen for his recurrences, and there was no evidence of disease for the vast majority of his 15-year course, during which he enjoyed excellent quality of life. This case emphasizes the importance of customizing care in MCC to give patients the best quality and quantity of life possible in their particular situation.