title: Identification of an anabolic selective androgen receptor modulator that actively induces death of androgen-independent prostate cancer cells.
abstract: Prostate cancer (PCa) initially responds to inhibition of androgen receptor (AR) signaling, but inevitably progresses to hormone ablation-resistant disease. Much effort is focused on optimizing this androgen deprivation strategy by improving hormone depletion and AR antagonism. However we found that bicalutamide, a clinically used antiandrogen, actually resembles a selective AR modulator (SARM), as it partially regulates 24% of endogenously 5α-dihydrotestosterone (DHT)-responsive genes in AR(+) MDA-MB-453 breast cancer cells. These data suggested that passive blocking of all AR functions is not required for PCa therapy. Hence, we adopted an active strategy that calls for the development of novel SARMs, which induce a unique gene expression profile that is intolerable to PCa cells. Therefore, we screened 3000 SARMs for the ability to arrest the androgen-independent growth of AR(+) 22Rv1 and LNCaP PCa cells but not AR(-) PC3 or DU145 cells. We identified only one such compound; the 4-aza-steroid, MK-4541, a potent and selective SARM. MK-4541 induces caspase-3 activity and cell death in both androgen-independent, AR(+) PCa cell lines but spares AR(-) cells or AR(+) non-PCa cells. This activity correlates with its promoter context- and cell-type dependent transcriptional effects. In rats, MK-4541 inhibits the trophic effects of DHT on the prostate, but not the levator ani muscle, and triggers an anabolic response in the periosteal compartment of bone. Therefore, MK-4541 has the potential to effectively manage prostatic hypertrophic diseases owing to its antitumor SARM-like mechanism, while simultaneously maintaining the anabolic benefits of natural androgens.
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA. Electronic address: azriel.schmidt@gmail.com.
authors.forename: Azriel
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Departments of Medicinal Chemistry, West Point, PA 19486, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Meissner
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gentile
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chisamore
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Opas
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Scafonas
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA; Departments of Medicinal Chemistry, West Point, PA 19486, USA; Departments of Molecular Profiling Merck & Co., West Point, PA 19486, USA.
authors.forename: Tara E
authors.initials: TE
authors.lastname: Cusick
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambone
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Pennypacker
authors.affiliation: Departments of Molecular Profiling Merck & Co., West Point, PA 19486, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Hodor
authors.affiliation: Departments of Medicinal Chemistry, West Point, PA 19486, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Perkins
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Bai
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Ferraro
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bettoun
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA.
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Wilkinson
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Alves
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Flores
authors.affiliation: Departments of Molecular Endocrinology, West Point, PA 19486, USA. Electronic address: jim.ray@takeda.com.
authors.forename: William J
authors.initials: WJ
authors.lastname: Ray
mesh_terms: D045930:Anabolic Agents / Q000737:chemistry / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001378:Azasteroids / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C000594012:(3-oxo-4-methylazaandrost-1-ene-17-yl)-2,2,2-trifluoroethyl ester carbamic acid; C410798:AR protein, human; D045930:Anabolic Agents; D059002:Androgen Receptor Antagonists; D000728:Androgens; D001378:Azasteroids; D002219:Carbamates; D012333:RNA, Messenger; D011944:Receptors, Androgen
keywords: AR antagonist; Androgen; Androgen receptor; MK-4541; PCa; Prostate cancer; SARM