My medicinal chemistry research program involves the design, synthesis, and biological evaluation of molecules that could potentially delay, inhibit, or cease carcinogenesis.
Discovery of new Forkhead box M1 (FOXM1) transcription factor modulators.
The forkhead box M1 (FOXM1) proteins are redox-responsive transcription factors essential for the expression of a wide variety of proteins required in cell mitosis. However, it has been determined that tumor cells undergo accelerated ERK-mediated FOXM1 phosphorylation, which leads to increased nuclear accumulation of FOXM1 and subsequent activation of the FOXM1-dependent transcriptional cascade. Genome-wide gene expression profiling of cancers has consistently identified FOXM1 as one of the most commonly upregulated genes in the early stages of carcinogenesis, and abnormal activation of FOXM1 gene expression is now regarded as one of the hallmarks of a wide variety of human malignancies. Accumulating evidence suggests that targeting FOXM1 can be a useful tool to decrease cancer resistance to a wide variety of chemotherapeutic agents, suggesting that FOXM1 modulators may be clinically useful drugs for the combinatorial treatment of cancer.
There are no reported drugs which directly bind to, and interfere with, the FOXM1 DNA binding domain in cancer cells. In this regard, the most common (still experimental) approaches described in the literature to decrease the in vitro and in vivo transcriptional activity of FOXM1, are (1) siRNA, and (2) proteasome inhibitors (which increase the expression of a negative regulator of FOXM1). Both of these techniques have significant disadvantages which makes them not suitable for the immediate development of therapeutic alternatives. This is where our research project takes off.
As part of an interdisciplinary research project aimed to validate the FOXM1 transcription factor as a drug target, we recently developed a molecular modeling approach in which we have accurately determined the binding energies of more than 3,000 FDA-approved drugs when docked (in silico) in the FOXM1a / DNA binding domain. We identified several promising lead compounds possessing varying degrees of direct binding affinities (unpublished data).
This specific aim of this research project is to generate essential information to determine if FOXM1 could be established as a “druggable” target, by testing known (FDA-approved) molecules which could directly interfere with the transcriptional activity of FOXM1. We also want to generate pharmacophores which could be used to design new chemically-modified drug derivatives with improved binding affinities for the FOXM1 DNA binding domain. Finally, the long-term goal of this research project is to generate data that will help us understand how to design potent/efficient drugs targeting not only the oncogenic FOXM1 protein but also transcription factors in general.