Aclimostat

Aclimostat (ZGN-1061) is a methionine aminopeptidase 2 (MetAP2) inhibitor. Aclimostat exhibits anti-obesity, anti-diabetic and ovarian cancer-related activities, and does not readily distribute to the central nervous system. Aclimostat acts on the active site of MetAP2 via irreversible covalent binding, and blocks enzyme activity through interactions with His231 and His339. Aclimostat regulates gene expression, reduces fat mass, plasma glucose, insulin levels, LDL-C, hs-CRP and leptin levels, while increasing adiponectin levels. Aclimostat can be used in research related to type 2 diabetes, overweight, obesity and ovarian cancer^{[1][2][3][4][5]}. In Vitro:Aclimostat (ZGN-1061) (6 nM; 2-24 h) induces nearly identical gene expression changes to Beloranib (HY-14811) in HepG2 cells after 2-hour and 24-hour exposures to 6 nM, with high concordance across genes linked to metabolic efficacy^[2].
Aclimostat (1-72 h) inhibits HUVEC proliferation with an EC₅₀ of 0.24 nM after continuous 72-hour exposure, but does not affect proliferation with short-term exposures of 4 hours or less at concentrations up to 50× the EC₅₀^[2].
Aclimostat (10 nM; 2 h, assessed over 72 h post-washout) shows transient target engagement in HUVECs, with covalent binding to the MetAP2 active site declining over 72 hours after a 2-hour 10 nM exposure, and no sustained accumulation of the MetAP2 substrate THX 1-6^[2].
Aclimostat (10 nM; 2 h, assessed over 72 h post-washout) shows transient target engagement in HepG2 cells, with covalent binding to the MetAP2 active site declining over 72 hours after a 2-hour 10 nM exposure^[2].
ZGN-1061 binds strongly to human MetAP2 with a docking score of -7.2 kcal/mol, interacting with key active site residues critical for MetAP2 function^[5].
Aclimostat (1-20 nM; 4-72 h) increases p21 and reduces TM protein levels in HUVECs, but does not affect these proteins with shorter 4-hour or 8-hour exposures, and does not alter p53, vWF, or PAI-1 levels at any tested concentration or time^[2].
ZGN-1061 (0-5000 nM; 1-6 days) inhibits proliferation of A2780 and SKOV3 ovarian cancer cells, with enhanced efficacy and lower IC₅₀ values in METAP2-overexpressing SKOV3 cells compared to control SKOV3 cells, and attenuated efficacy in METAP2-knockdown A2780 cells compared to control A2780 cells^[3]. In Vivo:Aclimostat (ZGN-1061) (0.3 mg/kg; s.c.; daily; 4 weeks) produces a 25% body weight reduction, improved glycemic control, and favorable metabolic changes in DIO insulin-resistant mice^[2].
ZGN-1061 (s.c.; daily; 28 days) reduces body weight by 25% and improves glucose and insulin levels in diet-induced obese insulin-resistant mice^[5].
Aclimostat (2 mg/kg; s.c.; every 3 days; 10 days) is well tolerated in healthy beagle dogs, with no adverse effects on coagulation markers or hematology parameters^[2].
Aclimostat (2-25 mg/kg; s.c.; every 3 days; 28 days) is well tolerated in Sprague Dawley rats, with minimal, reversible toxic effects^[2].
Aclimostat (0.1 mg/kg; s.c.; every 3 days; 4 weeks) exhibits potent activity against ovarian cancer in subcutaneous xenograft models, with significantly enhanced efficacy in METAP2-overexpressing tumors^[3].