1A-116

1A-116, a potent Rac1 inhibitor, is specific for W56 residues, can prevent EGF -induced Rac1 activation and block Rac1-P-Rex1 interaction. 1A-116 can induce apoptosis and inhibit cell proliferation, migration and cycle progression in a concentration-dependent manner. 1A-116 also demonstrates a high antimetastatic activity in vivo In Vitro 1A-116 (48 h) inhibits F3II and MDA-MB-231 cells proliferation in a concentration-dependent manner with IC 50 s of 4 μM and 21 μM, respectively. ? 1A-116 (1, 10 μM; 12 h) dramatically impaires Rac1 activation, and reduces Rac1-GTP intracellular levels in a concentration-dependent manner in F3II cells. ? 1A-116 (50, 100 μM; 12 h) blocks Rac1-P-Rex1 interaction. ? 1A-116 (20 μM; 5 h intervals over 25 h) inhibits LN229 cells proliferation in a circadian manner. ? 1A-116 (10 μM; 16 h) significantly reduces cell migration at 10 HPS which exhibits temporal dependence. (HPS: After the serum shock, the elapsed time (in hours) is recorded as the hours post-synchronization (HPS)). ? 1A-116 (20, 50 μM; 6 h) induces cells apoptosis and in a circadian-dependent manner. ? 1A-116 (100 nM) decreases the thickness of the epidermal layers of Vav2 and Rac1-mediated hyperplasia, but not the PAK1-mediated one, which exhibits the activity of inhibiting Rac1 at the GEF-Rac1 level. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Proliferation Assay Cell Line: MDA-MB-231, F3II, LN229 cells Concentration: 20 µM Incubation Time: 48 h; 5 h intervals over 25 h. Result: Inhibited cell proliferation in a concentration-dependent and circadian manner. Cell Viability AssayCell Line: Ker-CT human keratinocytes cells with oncogenic Vav2/Rac1 F28L/PAK1 Tyrosine 423 Concentration: 100 nM Incubation Time: Result: Inhibited Rac1 activity at the GEF-Rac1 level. Cell Migration AssayCell Line: LN229 cells Concentration: 10 µM Incubation Time: 16 h Result: Reduced cell migration at 10 HPS which exhibited temporal dependence. Apoptosis AnalysisCell Line: LN229 cells Concentration: 20, 50 µM Incubation Time: 6 h Result: Induced cells apoptosis and in a circadian-dependent manner. Western Blot AnalysisCell Line: F3II cells Concentration: 1, 10 µM Incubation Time: 12 h Result: Blocked Rac1-P-Rex1 interaction. Reduced Rac1-GTP intracellular levels in a concentration-dependent manner. In Vivo 1A-116 (3 mg/kg; i.v.; once a day for 21 days) demonstrates a high antimetastatic activity with about 60% formation reduction of total metastatic lung colonies in vivo and shows no apparent toxicity . ? 1A-116 (20 mg/kg; i.p.; once a day, 73 days for ZT12, 68 days for ZT3) increases survival time when treated at ZT12 compare to ZT3 in tumor-bearing mice. (ZT: Zeitgeber time 12 (ZT12) defined as the time of lights off (local time 7 p.m.) and ZT0 defined as lights on (local time 7 a.m.)). ? 1A-116 shows good oral availability. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Female BALB/c inbred mice (8 to 10-week-old; average 20 g) Dosage: 3 mg/kg Administration: Intravenous injection; once a day for 21 days. Result: Demonstrated a high antimetastatic activity. Animal Model: Male NIH Swiss foxN1(∆/∆) nude mice (2-month-old; GBM model). Dosage: 20 mg/kg Administration: Intraperitoneal injection (at ZT3, ZT12); once a day, 73 days for ZT12, 68 days for ZT3. Result: Increased survival time when treated at ZT12 compared to ZT3 in tumor-bearing mice. Form:Solid IC50& Target:IC50: 4 µM (F3II),21 µM (MDA-MB-231),Rac1, Apoptosis

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