UC2288

Cell permeable: yes

Toxicity: Standard Handling (A)

A cell-permeable compound that selectively downregulates the expression of p21 (~10 µM), independent of p53.expression, at either transcription or post-transcriptional level.

A cell-permeable phenylcyclohexyl-urea compound that downregulates cellular p21/Cip1/CKI/Waf1 protein level (by >95% in HCT116 cells after 24 h UC2288 treatment at 2.5 µM), presumably by means of a yet undetermined transcriptional or post-transcriptional regulation without affecting p21 cellular half-life or inhibiting the kinase activities of C-raf, B-raf^V600E, or VEGFR2 (IC₅₀ >10 µM). Dual telomerase and p21, but not p16 or p27 (gene = CDKN1A, CDKN2A, CDKN1B, respectively), knockdown/inhibition is demonstrated to effectively kill cancer cells both in vitro (% viability inhibition/% Annexin V+ cells induction = 20%/2% or 77%/55%, respectively, following telomerase inhibition by Imetelstat with or without 2.5 µM UC2288 for 24 h in HCT116 colon cancer cultures) and in mice in vivo (% tumor expansion suppression by UC2288 alone/Imetelstat alone/combined treatment = 13%/42%/90%/HCT116 and 4%/23%/92%/ACHN; 30 mg Imetelstat/kg via i.p. and/or 15 mg UC2288/kg via p.o. 3X/wk for 3 wk) by inducing p53- and E2F1-dependent PUMA expression, while p21 overexpression, p53 inactivation by mutation, shRNA-mediated E2F1 or PUMA downregulation abolishes such synergized cell killing. Likewise, reactivating mutant p53 activitiy by CP-31398 (Cat. No. 506166) treatment is reported to resensitize DLD1 (p53 S241F) and A375.S2 (p53 R273H & P309S) to p21 shRNA- & Imetelstat-induced apoptotic cell death and tumor growth inhibition.

Gupta, R., et al. 2014. Proc. Natl. Acad. Sci. USA111, E3062.
Wettersten, H.I., et al. 2013. Cancer Biol. Ther.14, 278.

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Use only fresh DMSO for reconstitution.

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