Chemical probes are versatile and unique tools for biomedical research. A chemical probe is simply a selective small-molecule modulator of protein function that allows the user to ask mechanistic and phenotypic questions about its molecular target in biochemical, cell-based or animal studies. Experiments involving selective inhibitors can help delineate key signaling pathway substrates and targets. Chemical probes have proven to be very impactful because they complement genetic approaches, such as CRISPR and RNAi, and also have unique advantages. Unlike knockout, knockdown, and dominant-negative approaches, inhibitors act immediately, allowing interrogation of the direct effects of signaling components and allow molecular tunability of function through structural changes. This dissertation describes the advances in the development, synthesis and application of chemical probes for evaluating, perturbing and establishing biological systems. Chapter 1 embarks on a selectivity analysis of a critical family of kinases (mitogen activated protein kinase, MAPKK) and progresses to our understanding of selectivity to the development of chemical probes. Chapter 2 stemmed from a novel structure-driven approach, which has yielded a unique non-toxic, anti-melanoma small molecule, which has been optimized to understand its role in cancer. Lastly, Chapter 3 describes the development of new probes through the use of natural products as a chemical starting point. Herein is discussed the work toward the total synthesis of a recently published class of new natural products shown to act as antagonists for a subset of 5-hydroxytryptamine (5-HT, serotonin) receptors as well as a series of analogs. Through chemical synthesis, computational modeling, biochemical and cellular-based experiments, our efforts on these projects have aided in the development of small molecule probes to study biological pathways, protein surroundings and the overall biological effects.

Last modified

• 01/29/2019

Creator

• Kristine Deibler

DOI

• https://doi.org/10.21985/N29X8N

Subject

• Chemistry

Keyword

• small molecules
• kinases
• chemical biology
• isoforms
• natural product

Date created

• 2017-01-01

Resource type

• Dissertation

Rights statement

• In Copyright