Prostate cancer (PCa) is currently the second-leading cause of cancer death in the United States. Although 1 in 6 men will develop this disease in their lifetime, mortality is generally attributed to the development of metastases. Inhibiting the early steps of the metastatic cascade could have a significant impact on themortality associated with PCa. However, all attempts to therapeutically inhibit metastasis have so far been unsuccessful. Our lead compound, genistein, a flavanoid commonly found in soy, has been shown to inhibit the early steps of the metastatic cascade in PCa models. However, genistein is an non-optimized natural product that demonstrates several off-target effects, including estrogenic activity and cell toxicity. Our goal is to synthesize new compounds which have enhanced anti-invasion activity but do not exhibit any of the off target effects associated with genistein. In particular, we will focus on the isoflavanones, which are a class of chiral molecules closely related to genistein that have not been previously studied for their biological activity.
Specific Aim 1 will focus on designing and synthesizing isoflavanones which have enhanced anti-invasion properties and reduced off-target effects. In particular, we will make structural modifications to the isoflavanone core to promote selective binding to the enzyme MEK4, which is a known member of the p38 MAP kinase signaling family and the biological target of genistein. We will then establish a structure-activity relationship (SAR) for these newly synthesized compounds by screening them for MEK4 inhibition, estrogenic activity, and cell toxicity. Isoflavanones that show increased inhibition of MEK4 but decreased off- target effects will then be tested for their biological efficacy in Specific Aim 2. In this Aim, we will test our compounds for anti-invasion activity in both PCa cell lines and murine models. We will also assess toxicity and other pharmacokinetic parameters in mice as part of this Aim. Our research has the potential to have a significant impact on public health, as it has a high likelihood of providing a potent and selective inhibitor of PCa metastasis. Given that metastatic disease is associated with such a high mortality rate, therapeutic interventions developed by our group hold the promise of significantly attenuating the effects of one of the leading causes of death in the United States.
|Farmer, Rebecca L; Scheidt, Karl A (2013) A Concise Enantioselective Synthesis and Cytotoxic Evaluation of the Anticancer Rotenoid Deguelin Enabled by a Tandem Knoevenagel/Conjugate Addition/Decarboxylation Sequence. Chem Sci 4:3304-3309|
|Crane, Erika A; Zabawa, Thomas P; Farmer, Rebecca L et al. (2011) Enantioselective synthesis of (-)-exiguolide by iterative stereoselective dioxinone-directed Prins cyclizations. Angew Chem Int Ed Engl 50:9112-5|
|Pavese, Janet M; Farmer, Rebecca L; Bergan, Raymond C (2010) Inhibition of cancer cell invasion and metastasis by genistein. Cancer Metastasis Rev 29:465-82|
|Farmer, Rebecca L; Biddle, Margaret M; Nibbs, Antoinette E et al. (2010) Concise syntheses of the abyssinones and discovery of new inhibitors of prostate cancer and MMP-2 expression. ACS Med Chem Lett 1:400-405|