Discovery of XB05, a potent antiproliferative agent and novel non-nucleoside inhibitor of DNA methyltransferase 1
Authors: Paula Bates, Gerald Hammond, Bo Xu, Jose Aponte, Mohammad Malik, Allison Martin, Enid Choi, Shelia Thomas, Lavona Casson, John Trent
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3298 

While investigating the biological properties of fluorine-containing organic molecules, we recently identified a novel small molecule, named XB05, which has tumor-selective antiproliferative activity. The molecule was submitted to the Developmental Therapeutics Program (DTP) at the National Cancer Institute (NCI) for testing in the 60 human tumor cell line screen. The results confirmed that XB05 has potent activity against a diverse range of cancer cell lines and also revealed an unusual activity profile, with a more than 1000-fold difference in GI50 values between the most and least sensitive lines. For example, colon, brain, renal, prostate and breast tumor cells were particularly sensitive to XB05, whereas other tumor types were substantially less responsive. The GI50 values for the sensitive cell lines were in the 10 - 100 nM range.    We analyzed the DTP data using the on-line COMPARE program, which allows comparison of the activity profile with the 43,000 compounds in the public database and which has been validated as grouping together agents with similar mechanisms of action, irrespective of their structure. When we used XB05 as a COMPARE seed, we found a strong correlation (Pearson coefficient 0.82) with a compound known as halomon.    Halomon is a marine-derived natural product, which has promising anticancer activity. However, its development has been severely limited because attempts to re-isolate it from its natural source or to develop an efficient synthesis have not enabled production of sufficient compound for testing. Halomon was recently reported to be an inhibitor of human DNA methyltransferase 1 (DNMT1), the enzyme responsible for maintaining DNA methylation after each cell division. DNMT1 is considered an attractive target for epigenetic therapy of cancer because methylation-induced silencing of tumor suppressor genes occurs frequently in cancer cells.    XB05 has now been tested in various cell-free and cell-based assays of DNA methylation. We find that it is a potent inhibitor of recombinant DNMT1 activity in vitro, with an IC50 of 10 nM. Moreover, XB05 could reactivate expression of several silenced tumor suppressor genes in cancer cells at concentrations of 100 nM or less.    In conclusion, XB05 is a novel agent with potent antiproliferative activity against cell lines derived from common cancers and a new type of DNMT1 inhibitor. XB05 is a mechanistic mimic of a natural product named halomon, but, in contrast to halomon, XB05 can be easily and inexpensively synthesized in large quantities. XB05 may also have substantial advantages over other existing DNMT inhibitors such as 5-azacytidine and decitabine. XB05 is more active than these agents in cell-free or cell-based DNMT assays and will likely be less toxic because it cannot be incorporated into DNA. Also, whereas 5-azacytidine and decitabine are rapidly degraded in aqueous solutions, XB05 appears to be completely stable.