Identification of anabolic selective androgen receptor modulators with reduced activities in reproductive tissues and sebaceous glands

Azriel Schmidt, Shun Ichi Harada, Donald B. Kimmel, Chang Bai, Fang Chen, Su Jane Rutledge, Robert L. Vogel, Angela Scafonas, Michael A. Gentile, Pascale V. Nantermet, Sheila McElwee-Witmer, Brenda Pennypacker, Patricia Masarachia, Soumya P. Sahoo, Yuntae Kim, Robert S. Meissner, George D. Hartman, Mark E. Duggan, Gideon A. Rodan, Dwight A. TowlerWilliam J. Ray

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 (IC50, 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 5α-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.

Original languageEnglish (US)
Pages (from-to)36367-36376
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number52
DOIs
StatePublished - Dec 25 2009

Fingerprint

Sebaceous Glands
Androgen Receptors
Modulators
Tissue
Dihydrotestosterone
Androgens
Genes
Ligands
Muscle
Bone
Virilism
Bone and Bones
Muscles
Seminal Vesicles
Microarray Analysis
Microarrays
Cytoplasmic and Nuclear Receptors
Hypertrophy
Inhibitory Concentration 50
Rats

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Identification of anabolic selective androgen receptor modulators with reduced activities in reproductive tissues and sebaceous glands. / Schmidt, Azriel; Harada, Shun Ichi; Kimmel, Donald B.; Bai, Chang; Chen, Fang; Rutledge, Su Jane; Vogel, Robert L.; Scafonas, Angela; Gentile, Michael A.; Nantermet, Pascale V.; McElwee-Witmer, Sheila; Pennypacker, Brenda; Masarachia, Patricia; Sahoo, Soumya P.; Kim, Yuntae; Meissner, Robert S.; Hartman, George D.; Duggan, Mark E.; Rodan, Gideon A.; Towler, Dwight A.; Ray, William J.

In: Journal of Biological Chemistry, Vol. 284, No. 52, 25.12.2009, p. 36367-36376.

Research output: Contribution to journalArticle

Schmidt, A, Harada, SI, Kimmel, DB, Bai, C, Chen, F, Rutledge, SJ, Vogel, RL, Scafonas, A, Gentile, MA, Nantermet, PV, McElwee-Witmer, S, Pennypacker, B, Masarachia, P, Sahoo, SP, Kim, Y, Meissner, RS, Hartman, GD, Duggan, ME, Rodan, GA, Towler, DA & Ray, WJ 2009, 'Identification of anabolic selective androgen receptor modulators with reduced activities in reproductive tissues and sebaceous glands', Journal of Biological Chemistry, vol. 284, no. 52, pp. 36367-36376. https://doi.org/10.1074/jbc.M109.049734
Schmidt, Azriel ; Harada, Shun Ichi ; Kimmel, Donald B. ; Bai, Chang ; Chen, Fang ; Rutledge, Su Jane ; Vogel, Robert L. ; Scafonas, Angela ; Gentile, Michael A. ; Nantermet, Pascale V. ; McElwee-Witmer, Sheila ; Pennypacker, Brenda ; Masarachia, Patricia ; Sahoo, Soumya P. ; Kim, Yuntae ; Meissner, Robert S. ; Hartman, George D. ; Duggan, Mark E. ; Rodan, Gideon A. ; Towler, Dwight A. ; Ray, William J. / Identification of anabolic selective androgen receptor modulators with reduced activities in reproductive tissues and sebaceous glands. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 52. pp. 36367-36376.
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AU - Chen, Fang

AU - Rutledge, Su Jane

AU - Vogel, Robert L.

AU - Scafonas, Angela

AU - Gentile, Michael A.

AU - Nantermet, Pascale V.

AU - McElwee-Witmer, Sheila

AU - Pennypacker, Brenda

AU - Masarachia, Patricia

AU - Sahoo, Soumya P.

AU - Kim, Yuntae

AU - Meissner, Robert S.

AU - Hartman, George D.

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AU - Ray, William J.

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