John A. Katzenellenbogen

Both the physiological and pathological actions of steroid hormones are mediated by their binding to specific, high-affinity binding receptor proteins found in hormone target tissues. We probe the molecular details of steroid hormone-receptor action using chemical and spectroscopic tools, and molecular and structural biology to understand how these interesting proteins work. We then use this understanding to design specific regulators for treating various diseases driven by these receptors, and novel agents for medical diagnostic procedures, including positron-emission tomographic (PET) imaging. Many of our studies are done in collaboration with structural, cell and molecular biologists, and with cancer and clinical medicine researchers.

Designed Hormones and Receptor Inhibitors

Based on our evolving understanding of receptor structure, we use organic synthesis and molecular biology to design ligands of novel structure, focusing on those having unusual biological activity and specificity. Some recently developed agents select between different cellular pathways of estrogen receptor signaling, providing many of the beneficial effects of estrogens while minimizing their undesirable effects.

Breast Cancer and Inflammatory and Neurological Disorders

Guided by structural studies of the estrogen receptor alpha, we are exploring new ways to design estrogen receptor antagonists that might have optimal activity in breast cancers that have become resistant to conventional hormone therapies. Our novel ligands for estrogen receptor beta show promising activity in animal models of endometriosis and multiple sclerosis and in some breast cancers, with promise for reversing established disease.

Probing Receptor Structure and Effects of Mutations.

We develop novel spectroscopic methods to analyze receptor structure, conformation, dynamics, and receptor-coregulator interactions, and to learn how these are affected by ligand structure. We use these tools to elucidate how mutational changes in these both interfere with or enhance their activities, thereby providing clues to how ligands might be designed to reverse these aberrant changes.

Radiopharmaceuticals and In Vivo Imaging Agents.

To image breast and prostate tumors in vivo by positron-emission tomography (PET), we are designing steroid analogs with exceptional binding affinity and selectivities for receptors in these cancers. When labeled with the radionuclide fluorine-18 (t_1/2 = 110 min), these agents provide clear images of tumors and their metastases based on their levels of estrogen, progesterone, or androgen receptors. These agents are being actively used in clinical research studies to guide and improve therapies for these cancers. One of our agents, FES (16α-[¹⁸F]Fluoroestradiol), was recently approved by the FDA for use in breast cancer.