John Albert Katzenellenbogen (born May 10, 1944) is an American Professor of Chemistry at the University of Illinois at Urbana-Champaign. He studies the development of novel agents for the treatment of hormone-responsive and non-responsive breast and prostate cancers and the design of estrogens and antiestrogens that have a favorable balance of beneficial versus detrimental effects. [1]
John Katzenellenbogen was born May 10, 1944, in Poughkeepsie, New York. His parents taught at Vassar College, his father a professor of art history and his mother a pianist. In 1958, his family moved to Baltimore, Maryland, where his father became Head of the Department of Art History at Johns Hopkins University [2] and his mother joined the faculty at Peabody Conservatory [3] and Goucher College. [4] He began playing the cello at age 10. Katzenellenbogen attended Gilman School [5] and held various summer jobs: in 1960, he worked at the Research Institute for Advanced Studies in the photosynthesis lab of Dr. Bessel Kok, [6] and, in 1961, he was a General Electric Student Research Fellow at Union College in Schenectady, New York. As an undergraduate at Harvard, he majored in chemistry, going on to complete a PhD in chemistry in 1969 at Harvard under the direction of Dr. E. J. Corey. [7]
Katzenellenbogen began his academic career as an Assistant Professor of Chemistry at the University of Illinois at Urbana-Champaign [8] in 1969 and was promoted to Associate Professor in 1975 and to Full Professor in 1979. He was named the Roger Adams Professor and subsequently the chaired Swanlund Professor of Chemistry. He was one of the first academic chemists to work in the field of chemical biology. His major research efforts have focused on the study of steroid hormones and their biological receptors, the estrogen receptor in particular.
Katzenellenbogen's research is highly collaborative, and he works with other scientists locally, nationally, and internationally. He has published more than 550 articles [9] and has trained over 130 PhD's and Postdoctoral Associates. He is a member of the American Association for the Advancement of Science and a fellow of the American Academy of Arts and Sciences, on whose National Council he served for many years. He has received numerous awards from scientific societies, including the Arthur C. Cope Scholar Award, [10] the E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances from the American Chemical Society, [11] the Endocrine Society's Fred Conrad Koch Lifetime Achievement Award, [12] which he shared with Dr. Benita Katzenellenbogen, and the Award for Outstanding Achievements in Chemistry in Cancer Research from the American Association for Cancer Research In 2018, Katzenellenbogen was inducted into the Medicinal Chemistry Hall of Fame of the American Chemical Society.
Katzenellenbogen developed the first affinity label for the estrogen receptor that was widely used to characterize its physical and biochemical properties, [13] [14] and he elucidated the metabolic activation of antiestrogens and characterized their sites of action. [15] He also pioneered the development of positron emission tomography (PET) imaging agents for estrogen, androgen, and progesterone receptors. [16] [17] [18] [19] The PET imaging agents he developed, FES, [20] FDHT, [21] and FFNP, [22] continue to be utilized to improve the prediction of patient response to endocrine therapy agents and to assist in the development of new cancer therapeutics. His more recent work is focused on developing novel antiestrogens effective against endocrine therapy-resistant forms of breast cancer [23] [24] and dissecting the mechanisms and signaling pathways that underlie the selective actions of estrogens in different target tissues. [25] [26] [27] [28]
Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.
Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).
Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women. It is taken by mouth.
Virgil Craig Jordan,, is a scientist with American and British citizenship specializing in drugs for breast cancer treatment and prevention. Currently, he is Professor of Breast Medical Oncology, and Professor of Molecular and Cellular Oncology at the University of Texas MD Anderson Cancer Center, Houston, Texas. Previously, he was Scientific Director and Vice Chairman of Oncology at the Lombardi Comprehensive Cancer Center of Georgetown University. Jordan was the first to discover the breast cancer prevention properties of tamoxifen and the scientific principles for adjuvant therapy with antihormones. More recently his work has branched out into the prevention of multiple diseases in women with the discovery of the drug group, selective estrogen receptor modulator (SERMs). Currently, he plans to develop a new Hormone Replacement Therapy (HRT) for post-menopausal women that prevents breast cancer and does not increase the risk of breast cancer.
Chlorotrianisene (CTA), also known as tri-p-anisylchloroethylene (TACE) and sold under the brand name Tace among others, is a nonsteroidal estrogen related to diethylstilbestrol (DES) which was previously used in the treatment of menopausal symptoms and estrogen deficiency in women and prostate cancer in men, among other indications, but has since been discontinued and is now no longer available. It is taken by mouth.
Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production. Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens. Antiestrogens are commonly used to stop steroid hormones, estrogen, from binding to the estrogen receptors leading to the decrease of estrogen levels. Decreased levels of estrogen can lead to complications in sexual development. Antiandrogens are sex hormone antagonists which are able to lower the production and the effects that testosterone can have on female bodies.
Brilanestrant (INN) is a nonsteroidal combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) that was discovered by Aragon Pharmaceuticals and was under development by Genentech for the treatment of locally advanced or metastatic estrogen receptor (ER)-positive breast cancer.
Estrogen deprivation therapy, also known as endocrine therapy, is a form of hormone therapy that is used in the treatment of breast cancer. Modalities include antiestrogens or estrogen blockers such as selective estrogen receptor modulators (SERMs) like tamoxifen, selective estrogen receptor degraders like fulvestrant, and aromatase inhibitors like anastrozole and ovariectomy.
Etacstil is an orally active, nonsteroidal, combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) that was developed for the treatment of estrogen receptor-positive breast cancer. It was shown to overcome antiestrogen resistance in breast cancer by altering the shape of the estrogen receptor, thus exhibiting SERD properties. Etacstil is a tamoxifen derivative and one of the first drugs to overcome tamoxifen-resistance. It is the predecessor of GW-7604, of which etacstil is a prodrug. This is analogous to the case of tamoxifen being a prodrug of afimoxifene (4-hydroxytamoxifen).
Endoxifen, also known as 4-hydroxy-N-desmethyltamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group as well as a protein kinase C (PKC) inhibitor. It is under development for the treatment of estrogen receptor-positive breast cancer and for the treatment of mania in bipolar disorder. It is taken by mouth.
Norendoxifen, also known as 4-hydroxy-N,N-didesmethyltamoxifen, is a nonsteroidal aromatase inhibitor (AI) of the triphenylethylene group that was never marketed. It is an active metabolite of the selective estrogen receptor modulator (SERM) tamoxifen. Unlike tamoxifen, norendoxifen is not a SERM, and instead has been found to act as a potent and selective competitive inhibitor of aromatase (Ki = 35 nM). Drugs with dual SERM and AI activity, such as 4'-hydroxynorendoxifen, have been developed from norendoxifen, and may have therapeutic potential as antiestrogens in the treatment of estrogen receptor-positive breast cancer.
Nitromifene (INN; also as the citrate salt nitromifene citrate (USAN), developmental code names CI-628, CN-5518, CN-55945) is a nonsteroidal selective estrogen receptor modulator (SERM) related to triphenylethylenes like tamoxifen that was never marketed. It is a mixture of (E)- and (Z)-isomers that possess similar antiestrogenic activity. The drug was described in 1966. Along with tamoxifen, nafoxidine, and clomifene, it was one of the earliest SERMs.
4'-Hydroxynorendoxifen is a synthetic, nonsteroidal antiestrogen of the triphenylethylene group. It is a dual selective estrogen receptor modulator (SERM) and aromatase inhibitor (AI), and was derived from tamoxifen, a SERM, and norendoxifen, a metabolite of tamoxifen that has been found to act as an AI. The drug has been suggested for potential development as a treatment for estrogen receptor (ER)-positive breast cancer. It was synthesized in 2015.
Benita S. Katzenellenbogen née Schulman is an American physiologist and cell biologist at the University of Illinois at Urbana-Champaign. She has studied cancer, endocrinology, and women's health, focusing on nuclear receptors. She also dedicated efforts to focusing on improving the effectiveness of endocrine therapies in breast cancer.
ERX-11, also known as ERα coregulator-binding modulator-11, is a novel antiestrogen and experimental hormonal antineoplastic agent which is being researched for the potential treatment of estrogen receptor-positive breast cancer. It is not a competitive antagonist of the estrogen receptor (ER) like conventional antiestrogens such as tamoxifen or fulvestrant; instead of binding to the ligand-binding site of the ER, ERX-11 interacts with a different part of the ERα and blocks protein–protein interactions of the ERα with coregulators that are necessary for the receptor to act and regulate gene expression. It was designed to bind to the coregulator binding region of the ERα and inhibit the ERα/coactivator interaction, although its precise binding site and mode of action have yet to be fully elucidated and understood. Nonetheless, it is clear that ERX-11 binds within the AF-2 domain of the ERα.
Ann M. Nardulli was an American endocrinologist known for her research into the role of estrogen in breast cancer.
11β-Chloromethylestradiol is a synthetic steroidal estrogen which was never marketed. It has very high affinity for the estrogen receptor and dissociates from it relatively slowly. It was originally thought that 11β-CME2 might be a covalent ligand of the estrogen receptors, but its binding was subsequently shown to be fully reversible. The relative binding affinity of 11β-CME2 for the estrogen receptors ranges from 230 to 3,320% of that of estradiol depending on the study. 11β-CME2 also has about 14% of the relative binding affinity of estradiol for sex hormone-binding globulin (SHBG). The compound has been developed as a radiolabel for the ERs.
Robert Clarke is a Northern Irish oncology researcher and academic administrator. He is the executive director of The Hormel Institute, a professor of biochemistry, Molecular Biology and Biophysics at the University of Minnesota, and an Adjunct Professor of Oncology at Georgetown University.
Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.