Disease relevance of SARM1

The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH)[1] .Biochemical markers of bone turnover revealed an early increase of bone resorption in androgen-deficient rats that was repressed in ORX animals treated with the oral SARM, LGD2226, during a 4-month treatment period[1] .In recent studies, we have used a skeletally mature orchiectomized (ORX) male rat as an animal model of male hypogonadism for assessing the efficacy of LGD2226, a nonsteroidal, non-aromatizable, and non-5alpha-reducible SARM[1] .High impact information on SARM1

• TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM [2].
• Unlike all known TIR-domain adapter proteins, overexpression of the human TIR-1 homologue, SARM, in mammalian cells was not sufficient to induce expression of NF-kappaB or IRF3-dependent reporter genes that are activated by Toll-like receptor signaling [3].
• These integrated homology modeling and CoMFA studies identified critical amino acids for SARM interactions and provided QSAR data as the basis for mechanistic studies of AR structure, function, and design of optimized SARMs[1] .This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5alpha-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH[1] .A 0.4-kb antisense transcript was coordinately expressed with the SARM gene in the kidney and liver, while in the brain and malignant cell lines, it appeared independent of SARM gene transcription [4].

Biological context of SARM1

• The mouse SARM gene was located on a mouse chromosome 11 BAC clone (AC002324) [4].

We examined the pharmacokinetics and metabolism of S-1 in rats as a component of our preclinical development of this compound and continued interest in structure-activation relationships for SARM action[1] .Associations of SARM1 with chemical compoundsThere is also interest in developing selective androgen receptor modulators (SARM) that can achieve AR blockade without causing the increased testosterone levels produced by the nonsteroidal antiandrogens currently in use[1] .Associations of SARM1 with chemical compounds

Other interactions of SARM1

• Two additional adaptors are present in humans, termed Trif-related adaptor molecule (TRAM) and sterile alpha and HEAT-Armadillo motifs (SARM) [5].
• Both Samd2 and Smad3 mediate TGFbeta1 signaling as downstream mediators in MSCs [6].

References