An inhibitor of the p53-HDM-2 interaction
IC50: 2 nM and 20 nM for A-498 and TK-10, respectively
A series of naturally occurring and synthetic compounds containing one or more thiophene moieties have been tested in the NCI Anticancer Drug Screen and have demonstrated differential antiproliferative activity. Thiophene derivatives as a class exhibit very similar patterns of differential sensitivity, the molecular basis for which is not clear. The compound 2,5-bis(5-hydroxymethyl-2-thienyl) furan (NSC 652287), is the most potent thiophene derivative and has been selected as the lead compound for mechanistic studies.
In vitro: A number of cell lines showed a striking differential sensitivity to NSC 652287 when compared with the other cell lines in the panel, with GI50 values of 10–60 nM. The compound was found to decrease the initial number of cells by 50% (LC50) at a concentration of 100 nM in the A-498 cell line, compared with ~100 mM for the majority of the tumor cell lines. The A-498 and TK-10 cell lines were particularly sensitive to NSC 652287-induced cytotoxicity compared with ACHN and UO-31 cell lines [1].
In vivo: NSC 652287 was evaluated against A-498 tumor cell xenografts grown subcutaneously in nude mice. When NSC 652287 was administered twice a day, all three doses resulted in complete tumor regression in 100% of the treated mice by the end of the third treatment period. The tumors did not regrow during the remaining 40 days of the study, and no gross evidence of toxicity was observed. Studies with xenografts derived from other sensitive cell lines including the renal CAKI-1, melanoma UACC-257, ovarian OVCAR-5, and colon HCC-2998, showed moderate or minimal in vivo activity [2].
Clinical trials: Currenlty no clinical data are available.
Reference:
[1] Rivera MI, Stinson SF, Vistica DT, Jorden JL, Kenney S, Sausville EA.?? Selective toxicity of the tricyclic thiophene NSC 652287 in renal carcinoma cell lines: differential accumulation and metabolism. Biochem Pharmacol. 1999;57(11):1283-95.
| Cell experiment [1]: | |
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Cell lines |
Human renal tumor cell lines |
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Preparation method |
The solubility of this compound in DMSO is >14.6mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
48-hr |
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Applications |
NSC 652287 (48-hr) inhibited cell growth with the GI50 values of 10–60 nM in the tumor cell lines. The A-498 and TK-10 cell lines were particularly sensitive to NSC 652287-induced cytotoxicity with the IC50 values of 2 nM and 20 nM, respectively. |
| Animal experiment [1,2]: | |
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Animal models |
Nude mice bearing A-498 tumor cell xenografts, HCT116 tumor xenografted mouse model |
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Dosage form |
Intravenous injection, 7 hr apart, every 4 days for 12 days |
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Application |
NSC 652287 (44.5 mg/kg, 66.7 mg/kg, 100 mg/kg) resulted in complete tumor regression in 100% of the treated mice by the end of the third treatment period. Intraperitoneal administration of NSC 652287 was well tolerated in mice after, with no observable weight loss at doses up to 10 mg/kg during 1 month. NSC 652287 (0.1 mg/kg, five injections) suppressed the growth of the HCT116 tumors by 40%. NSC 652287 (1 or 10 mg/kg) showed strong antitumor activity. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Rivera M I, Stinson S F, Vistica D T, et al. Selective toxicity of the tricyclic thiophene NSC 652287 in renal carcinoma cell lines: differential accumulation and metabolism[J]. Biochemical pharmacology, 1999, 57(11): 1283-1295. [2]. Issaeva N, Bozko P, Enge M, et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors[J]. Nature medicine, 2004, 10(12): 1321. | |
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