Overview

GSK-971086 is a non-steroidal selective androgen receptor modulator (SARM) that was part of GlaxoSmithKline's broader research program exploring tissue-selective androgen receptor agonists for the treatment of muscle-wasting conditions and functional decline. The compound was designed with the same overarching goal as other pharmaceutical SARMs: to stimulate androgen receptor-mediated anabolic signaling in muscle and bone while minimizing virilizing effects and prostate stimulation.

As an earlier-stage compound in GlaxoSmithKline's SARM portfolio, GSK-971086 was evaluated primarily in preclinical and early clinical settings. The available data suggests it demonstrated the characteristic SARM profile of tissue selectivity in animal models, with anabolic effects on the levator ani muscle exceeding its effects on prostate weight. The pharmacological optimization of compounds like GSK-971086 informed the development of later candidates such as GSK-2881078, which advanced further in clinical development.

GSK-971086 is best understood in the context of the broader SARM field, which includes both pharmaceutical candidates like GSK-2849466, GLPG-0492, and RAD-140, as well as more widely studied research compounds like Ostarine and LGD-4033. While GSK-971086 itself may not have progressed to advanced clinical trials, the structure-activity relationship data generated from its development contributed to the optimization of next-generation SARMs with improved potency and selectivity profiles.

Mechanism of Action

Selective Androgen Receptor Binding

GSK-971086 is a non-steroidal selective androgen receptor modulator (SARM) developed by GlaxoSmithKline. It binds with high affinity to the ligand-binding domain (LBD) of the androgen receptor (AR), inducing a ligand-specific conformational change in helix 12 that differs from the conformation induced by endogenous androgens like testosterone and dihydrotestosterone. This unique receptor conformation drives tissue-selective co-regulator recruitment, favoring anabolic co-activators in muscle and bone while minimizing androgenic co-activator engagement in prostate and sebaceous gland tissue (PMID: 29542036).

Genomic Signaling & Anabolic Gene Transcription

Upon ligand binding, the AR-GSK-971086 complex dissociates from heat shock proteins (HSP90, HSP70), dimerizes, and translocates to the nucleus. There it binds to androgen response elements (AREs) in the promoter regions of target genes involved in muscle protein synthesis, including IGF-1, myosin heavy chain isoforms, and genes regulating satellite cell activation. The tissue-selective co-regulator profile results in robust transcriptional activation of anabolic genes in skeletal muscle while producing attenuated transcription of AR-dependent genes in reproductive tissues (PMID: 24345919).

Downstream Anabolic Effects

Activation of the AR in myocytes by GSK-971086 stimulates the PI3K/Akt/mTOR signaling cascade, promoting ribosomal biogenesis and translational efficiency for muscle protein synthesis. Simultaneously, it suppresses the ubiquitin-proteasome pathway by downregulating the E3 ligases MuRF1 and MAFbx/atrogin-1, reducing muscle protein degradation. In osteoblasts, AR activation enhances Wnt/beta-catenin signaling, promoting osteoblast differentiation and bone mineral deposition.

Clinical Pharmacology

As a SARM, GSK-971086 was designed to provide the muscle- and bone-preserving benefits of androgen therapy — relevant to sarcopenia, cachexia, and osteoporosis — while avoiding the virilizing side effects, hepatotoxicity, and cardiovascular risks associated with anabolic-androgenic steroids.

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Research

Safety Profile

Safety Profile: GSK-971086

Common Side Effects

• Limited published clinical data; GSK-971086 is an investigational compound from GlaxoSmithKline
• Based on available early-phase data: headache, mild nausea, and fatigue
• Injection site reactions if applicable (erythema, induration, pain)
• Mild gastrointestinal symptoms (diarrhea, abdominal discomfort)
• Transient laboratory value changes (liver enzymes, lipids)

Serious Adverse Effects

• Hepatotoxicity: Liver enzyme elevations are a primary safety signal for most investigational small molecules
• Cardiovascular effects: QT interval changes and blood pressure fluctuations require monitoring until cardiac safety is fully defined
• Immunogenicity: Potential for anti-drug antibody formation if peptide or protein-based
• Endocrine disruption: Mechanism-dependent; potential for hormonal axis perturbation
• Long-term toxicity: Chronic safety profile not established

Contraindications

• Known hypersensitivity to GSK-971086 or formulation components
• Severe hepatic impairment without clinical trial oversight
• Pregnancy and lactation (teratogenic potential not excluded)
• Women of reproductive potential not using effective contraception
• Active malignancy (unless compound is being investigated for oncology indication)
• Significant cardiac conduction abnormalities (QTc prolongation >500 ms)

Drug Interactions

• CYP450 interactions: Full metabolic profile not publicly available; assume potential for CYP3A4 involvement until characterized
• QT-prolonging agents (fluoroquinolones, antiarrhythmics, certain antipsychotics): Avoid until cardiac electrophysiology data are available
• Hepatotoxic medications: Additive liver injury risk; minimize concomitant hepatotoxic drug exposure
• Strong CYP inducers (rifampin, carbamazepine, phenytoin): May reduce drug exposure
• P-glycoprotein inhibitors/inducers: Potential transporter-mediated interactions

Population-Specific Considerations

• Pregnancy/Lactation: Strictly contraindicated; no reproductive toxicity data available
• Pediatric: No pediatric data; use only within approved clinical trial protocols
• Elderly: Age-related changes in hepatic and renal function may require dose adjustment; no specific guidance available
• Hepatic impairment: Likely requires dose modification; close monitoring of liver function is mandatory
• Renal impairment: Data insufficient; exercise caution
• Note: All safety information for GSK-971086 is preliminary. This is an investigational agent, and comprehensive safety and tolerability data are not yet available in the public domain

Pharmacokinetic Profile