生物活性

• 靶点	ASK1 pIC50:8.3

• 描述Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase (MAP3K) family member which plays a role in the mammalian cell stress response and the induction of apoptotic cell death. Selonsertib (GS-4997) is a highly selective ASK1 inhibitor with potential anti-inflammatory, antineoplastic and anti-fibrotic activities, the IC50 value of which is 3.2nM, involved in a variety of conditions like fibrosis, oxidative stress. In In vivo murine model, treatment with GS-4997 reduced fbrosis and steatosis, thus ameliorating the liver disease, thereby suggesting ASK1 inhibition as the promising therapeutic approach. Pharmacokinetics of GS-4997 has been already evaluated in phase 1 clinical study in adult with normal or impaired liver function (NCT02509624) and are currently registered in other clinical trials. Additionally, another clinical trial has been launched recently evaluating GS-4997 in patients with nonalcoholic steatohepatitis (NASH) and fibrosis . A randomized phase 2 trial evaluated two doses of selonsertib alone or in combination with SIM or SIM alone for the treatment of NASH with moderate to severe liver fibrosis (stages 2 or 3), individuals treated with selonsertib for 24 weeks had reduction in fibrosis stage and improvement in liver stiffness measure by magnetic resonance elastography and had a decreased chance of progressing to cirrhosis. Overall, GS-4997 was well tolerated with no dose-related increase in the incidence of treatment-emergent adverse events or serious adverse events . In a phase 2 placebo-controlled clinical trial that included 75 patients withT2DM and 3/4 DKD, who received treatment with GS-4997 (18 mg, 6 mg, 2mg orally once daily) alone or placeto alone as the control for 48 weeks. GS-4997 was regarded delineating study population, efficacy outcomes, treatment period and statistical methods represent innovative attempts to resolve challenges specific to DKD study design .
• 作用机制GS-4997 binds to the catalytic domain of ASK1 in an ATP-competitive manner thus preventing phosphorylation and activation.

• 动物研究
  剂量	Mice: 30 mg/kg[3] (p.o.), 15 mg/kg[4] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02781584	Nonalcoholic Steatohepatitis (... more >>NASH) Collapse <<	Phase 2	Recruiting	July 2019	United States, California ... more >> Recruiting Los Angeles, California, United States Recruiting Palo Alto, California, United States Recruiting San Diego, California, United States United States, Florida Florida Research Institute Recruiting Lakewood Ranch, Florida, United States, 34211 United States, Tennessee Recruiting Germantown, Tennessee, United States Recruiting Nashville, Tennessee, United States United States, Texas Recruiting Austin, Texas, United States Active, not recruiting Live Oak, Texas, United States Recruiting San Antonio, Texas, United States New Zealand Active, not recruiting Grafton, Auckland, New Zealand Collapse <<
  NCT02234141	Pulmonary Arterial Hypertensio... more >>n Collapse <<	Phase 2	Completed	-	-
  NCT03449446	Nonalcoholic Steatohepatitis	Phase 2	Active, not recruiting	October 2019	-

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