Results in Chemistry (Dec 2023)
Identifying dual acting small molecule inhibitors for potential treatment of castration-resistant prostate cancer
Abstract
Despite application of the best available treatments, prostate cancer frequently progresses to a more advanced, drug-resistant form called metastatic castration-resistant prostate cancer. As part of our approach to the development of new treatment options we have recently identified some peptides with a novel mode of action. These peptides indirectly inhibit the histone methyltransferase activity of the polycomb repressive complex (PRC2) through their binding to the SUZ12 regulatory protein of this complex. In addition, these peptides show a second unique activity by blocking expression of the androgen receptor that plays an important role in prostate cancer cell proliferation. This dual mode of action leads to significant cytotoxicity against prostate cancer cells. To develop these peptides into active small molecules a custom fragment library was screened to identify new lead compounds that could displace the active peptides from the SUZ12 binding site. Several leads have now been identified that bind to SUZ12 and displace a bound peptide at concentrations in the low micromolar range. These lead compounds are also cytotoxic against prostate cancer cells and show the same dual mode of action previously seen with the novel peptides.
