title: Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer.
abstract: Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT improves overall and disease-free survival rates, but long-term therapy is associated with severe side effects of androgen and estrogen depletion including hot flashes, weight gain, depression, and osteoporosis. Effective hormone reduction can be achieved without estrogen deficiency-related side effects by using therapy with estrogenic compounds. However, cardiovascular complications induced by estrogens coupled with the availability of LHRH agonists led to discontinuation of estrogen use for primary androgen deprivation therapy in the 1980s. New treatments for prostate cancer that improve patient outcomes without the serious estrogen deficiency-related toxicities associated with ADT using LHRH analogs are needed. Herein we describe a novel nonsteroidal selective estrogen receptor-α agonist designed for first-line therapy of advanced prostate cancer that in animal models induces medical castration and minimizes many of the estrogen deficiency-related side effects of ADT. The present studies show that orally administered GTx-758 reversibly suppressed testosterone to castrate levels and subsequently reduced prostate volume and circulating prostate-specific antigen in relevant preclinical models without inducing hot flashes, bone loss, thrombophilia, hypercoagulation, or increasing fat mass.
authors.affiliation: Preclinical Research and Development, GTx, Inc., 3 North Dunlap Street, Memphis, Tennessee 38163, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Coss
authors.forename: Amanda
authors.initials: A
authors.lastname: Jones
authors.forename: Deanna N
authors.initials: DN
authors.lastname: Parke
authors.forename: Ramesh
authors.initials: R
authors.lastname: Narayanan
authors.forename: Christina M
authors.initials: CM
authors.lastname: Barrett
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Kearbey
authors.forename: Karen A
authors.initials: KA
authors.lastname: Veverka
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Morton
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Steiner
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology*; D001823:Body Composition; D049109:Cell Proliferation; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D006801:Humans; D007986:Luteinizing Hormone / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051381:Rats; D013739:Testosterone / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C000603456:3-fluoro-N-(4-fluorophenyl)-4-hydroxy-N-(4-hydroxyphenyl)benzamide; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; C554248:N,N-diphenylbenzamide; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone