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Our lab is interested in the discovery of new chemical matter to study and treat various types of cancer. We use both high throughput screening and natural products as starting points in our discovery efforts, which we further modify to uncover structure-activity relationships (SAR). Our studies have provided new molecular probes capable of interrogating biological function (such as ML-141) and have the potential to serve as new therapeutic agents (metarrestin). Additionally, dissection and modification of naturally occurring compounds allows us to gain insight into structural components responsible for the desired biological activity (see C13-epi-taxol) that provide guidance in the development of more potent analogs (see withalongolide A derivatives). More details regarding ongoing projects in this area can be found below.
Development of Tool Compounds and New Thereaputics
De Novo Synthesis
suppreses metastasis of cancer, set for clinical trials
tool to study Cdc42 GTPase, used in over 300 publications
withalongolide A derivative
cytotoxic activity against cancer cells
The overexpression of the RNA binding protein Hu antigen R (HuR) has been implicated in several forms of cancer as well as other malignancies including inflammatory, cardiovascular, muscle, kidney, and liver diseases. With the support from the laboratory of Dr. Liang Xu (University of Kansas) we identified small molecule inhibitors of HuR by using high throughput screening. Subsequent validation studies revealed that coumarin-derived small molecules such as CMLD-2 are capable of disrupting the HuR-mRNA interaction by competitively binding HuR. Our current efforts use computer aided drug design to identify new inhibitors of HuR.
High Throughput Screening
Computer Aided Drug Design
Ki = 0.35 μM
In collaboration with Dr. Emily Scott at the University of Michigan, we are developing small molecules for the treatment of late-stage prostate cancer. Much of our recent work has focused on improving the efficacy of abiraterone, a first-class inhibitor of cytochrome P450 17A1 (CYP17A1), using structure-based drug design. These efforts have resulted in a new analog that inhibits its primary drug target more selectively than the similar cytochrome P450 21A2 (CYP21A2). In the future, we aim to demonstrate that this compound offers a clinical advantage over abiraterone in the form of reduced adverse side effects, which include hypertension, hypokalemia, and edema.
CYP17A1 IC50 = 4.94 nM
CYP21A2 IC50 = 32.4 nM
CYP17A1 IC50 = 16.5 nM
CYP21A2 IC50 = 1390 nM
Suggestions for further reading
Synthesis of 13-epi-Taxol
Synthesis and Cytotoxicity of Semisynthetic Withalongolide A Analogues
Ml-141 and its characterization as a Cdc42 GTPase Inhibitor
HuR-targeted Small Molecule Inhibitor Exhibits Cytotoxicity Towards Human Lung Cancer Cells
Structure-based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2
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