Abstract
Androgen replacement therapy is a promising strategy for the treatment of frailty; however, androgens pose risks for unwanted effects including virilization and hypertrophy of reproductive organs. Selective Androgen Receptor Modulators (SARMs) retain the anabolic properties of androgens in bone and muscle while having reduced effects in other tissues. We describe two structurally similar 4-aza-steroidal androgen receptor (AR) ligands, Cl-4AS-1, a full agonist, and TFM-4AS-1, which is a SARM. TFM-4AS-1 is a potent AR ligand (IC(50), 38 nm) that partially activates an AR-dependent MMTV promoter (55% of maximal response) while antagonizing the N-terminal/C-terminal interaction within AR that is required for full receptor activation. Microarray analyses of MDA-MB-453 cells show that whereas Cl-4AS-1 behaves like 5alpha-dihydrotestosterone (DHT), TFM-4AS-1 acts as a gene-selective agonist, inducing some genes as effectively as DHT and others to a lesser extent or not at all. This gene-selective agonism manifests as tissue-selectivity: in ovariectomized rats, Cl-4AS-1 mimics DHT while TFM-4AS-1 promotes the accrual of bone and muscle mass while having reduced effects on reproductive organs and sebaceous glands. Moreover, TFM-4AS-1 does not promote prostate growth and antagonizes DHT in seminal vesicles. To confirm that the biochemical properties of TFM-4AS-1 confer tissue selectivity, we identified a structurally unrelated compound, FTBU-1, with partial agonist activity coupled with antagonism of the N-terminal/C-terminal interaction and found that it also behaves as a SARM. TFM-4AS-1 and FTBU-1 represent two new classes of SARMs and will allow for comparative studies aimed at understanding the biophysical and physiological basis of tissue-selective effects of nuclear receptor ligands.
Highlights
Androgens, primarily testosterone (T)7 and its more potent derivative, 5␣-dihydrotestosterone (DHT), induce male reproductive physiology and secondary sexual traits such as facial hair and deepened voice
Current androgens induce male secondary sexual traits such as acne and hirsutism, an effect known as virilization, [12] and pose concerns related to unwanted effects in the prostate and other reproductive organs [13,14,15]
We hypothesized that all androgen receptor (AR) ligands capable of significant transactivation would produce anabolism, but selective androgen receptor modulators (SARMs) would create a unique receptor conformation that could be detected in other biochemical experiments
Summary
Microarray analyses of MDA-MB-453 cells show that whereas Cl-4AS-1 behaves like 5␣-dihydrotestosterone (DHT), TFM-4AS-1 acts as a geneselective agonist, inducing some genes as effectively as DHT and others to a lesser extent or not at all This gene-selective agonism manifests as tissue-selectivity: in ovariectomized rats, Cl-4AS-1 mimics DHT while TFM-4AS-1 promotes the accrual of bone and muscle mass while having reduced effects on reproductive organs and sebaceous glands. Because these individuals are often incompletely virilized, we hypothesized that those AR ligands that do not promote the conformation required for the N/C interaction would have reduced virilizing effects Using this approach, we identified two new distinct anabolic SARMs, TFM-4AS-1 and FTBU-1, which display agonism in bone and muscle while having reduced effects on reproductive organs and sebaceous glands. We provide evidence suggesting that the molecular basis of these differential responses is gene-selective agonism
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