HDM-2 (human double minute-2; MDM-2 in mouse) is a key negative regulator of p53 that binds to and targets p53 for proteasomal degradation. Overexpression of HDM-2 in some tumors leads to inactivation of p53 thereby allowing tumor cells to escape p53-induced apoptosis.¹ RITA (reactivation of p53 and induction of tumor cell apoptosis) is a small molecule inhibitor of p53-HDM-2 interaction that can reactivate the tumor suppressor function of wild-type p53.² It binds to p53 with an apparent K_d of 1.5 nM and prevents interaction with HDM-2 resulting in p53 stabilization, accumulation and activation.² RITA potently inhibits the growth of a variety of cancer cell lines in the sub-micromolar range, inducing both DNA-protein and DNA-DNA cross links in human renal cancer cells.³ RITA reduced tumor size by 90% at a dose of 10 mg/kg in SCID mice bearing HCT116 tumors, and caused complete regression of A-498 tumor cell xenografts in nude mice at a dose of 45 mg/kg.^2,4

1 Chène, P. Inhibiting the p53-MDM2 interaction: An important target for cancer therapy. Nat Rev Cancer 3 102-109 (2003).

2 Issaeva, N., Bozko, P., Enge, M., et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activities p53 function in tumors. Nat Med 10(12) 1321-1328 (2004).

3 Nieves-Neira, W., Rivera, M.I., Kohlhagen, G., et al. DNA protein cross-links produced by NSC 652287, a novel thiophene derivate active against human renal cancer cells. Mol Pharmacol 56 478-484 (1999).

4 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. Biochem Pharmacol 57 1283-1295 (1999).

Chène, P. Inhibiting the p53-MDM2 interaction: An important target for cancer therapy. Nat Rev Cancer 3 102-109 (2003).

Issaeva, N., Bozko, P., Enge, M., et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activities p53 function in tumors. Nat Med 10(12) 1321-1328 (2004).

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. Biochem Pharmacol 57 1283-1295 (1999).

Nieves-Neira, W., Rivera, M.I., Kohlhagen, G., et al. DNA protein cross-links produced by NSC 652287, a novel thiophene derivate active against human renal cancer cells. Mol Pharmacol 56 478-484 (1999).

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RITA is available in the following screening library:

• Bio-active Lipid I Screening Library (96-Well)