Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Objective To assess whether propofol call induce stable psychic dependence in the rats by self-administration experiment. Methods Twenty-four male SD rats 14 weeks old weighing 240一270 mg were studied. Anesthesia was performed with intraperitoneal injection of 3%sodium pentoharbitsl 40 ms/kg and atropine 03 mg/kg.A catheter wag inserted into the right external jugular vein. Penicillin(100 000 U)0.2 ml wag injected through the external jugular vein for anti-infection and heparin sodium(50U/ml)0.1 ml for anticoagulation. The self-administration experiment of 14 days was started after the 7 days of recovery. All the rats were randomly divided into 4 groups(n=6 each):contontrol group(C),propofol 0.56 mg/kg/l group(P1),propofol 1.00 mg/kg group(P2)and pmpofol 1.70 ms/kg group(P3).The experimental events were controlled by a computer with 50 times of the maximum injection per day.The times ofactive and inactive nose-poke response and times of drug iniection were recorded per day.Results Compared with group C and P1,the times of active nosepoke response and injections were significantly increased in group P2 and P3(P<0.01).The times of active nosepoke response and injections per day were significantly increased in group P3 than in group P2(P(0.01).There was no significant difference in the times of active nose-poke response and injections between group C and P1.There was no significant difference in inactive nose-poke resporme between the 4 groups.And the total daily doses of propofol injected in the last 3 days were significantly increased in a dose-dependent manner.Conclusion Propefol can induce the development of psychological dependence in rata and it is related to the dosage.