Development of selective androgen receptor modulators (SARMs)

Abstract

The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits.

Keywords: Androgens; Breast cancer; Coactivators; Duchenne muscular dystrophy (DMD); Kinase; Muscle wasting; Selective androgen receptor modulators (SARMs); Stress urinary incontinence.

Figure 1

Structures of selected SARMs from various pharmaceutical companies.

Figure 2

PC-3 (prostate cancer cells) or C2C12 (muscle cells) cells were transfected with CMV-hAR, GRE-LUC, CMV-LUC, and coactivator SRC-1 using Amaxa electroporator. Cells were treated 24 hours after transfection and luciferase assay was performed 48 hours after transfection. The results show that while SARM increased the AR transactivation significantly in C2C12 cells even at lower concentrations (1 nM), it increased the AR transactivation in prostate cancer cells only at higher concentrations (10 nM).

Figure 3. Recruitment of both coactivator and corepressor in a SARM complex

LNCaP cells were serum starved for 2 days and treated with vehicle, 10 nM DHT, or 100 nM arylpropionamide SARM for 4 hours. Cells were fixed with 1% formaldehyde to cross-link protein:DNA complex and immunonoprecipitation was performed with SRC-1 or NCoR antibodies. DNA:protein complex crosslink was reversed, DNA extracted, and realtime PCR with primers and probes specific to the PSA enhancer ARE was performed.

Figure 4. Model

While a full agonist such as DHT promotes a full agonistic conformation in prostate environment by interacting with coactivators, a SARM promotes a partial agonistic conformation by promoting a complex that contains coactivators and corepressors.