Journal
CANCER RESEARCH COMMUNICATIONS
Volume 3, Issue 7, Pages 1378-1396Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2767-9764.CRC-23-0111
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A group of small molecules with imidazopyridine scaffolds have been identified as more potent inhibitors of breast cancer cell growth and activators of p53, resulting in cell cycle arrest and apoptosis.
The pro-oncogenic activities of estrogen receptor alpha (ER alpha) drive breast cancer pathogenesis. Endocrine therapies that impair the production of estrogen or the action of the ER alpha are therefore used to prevent primary disease metastasis. Although recent successes with ER alpha degraders have been reported, there is still the need to develop further ER alpha antagonists with additional properties for breast cancer therapy. We have previously described a benzothiazole compound A4B17 that inhibits the proliferation of androgen receptor-positive prostate cancer cells by disrupting the interaction of the cochaperone BAG1 with the AR. A4B17 was also found to inhibit the proliferation of estrogen receptor-positive (ER+) breast cancer cells. Using a scaffold hopping approach, we report here a group of small molecules with imidazopyridine scaffolds that are more potent and efficacious than A4B17. The prototype molecule X15695 efficiently degraded ER alpha and attenuated estrogen-mediated target gene expression as well as transactivation by the AR. X15695 also disrupted key cellular protein-protein interactions such as BAG1-mortalin (GRP75) interaction as well as wild-type p53-mortalin or mutant p53-BAG2 interactions. These activities together reactivated p53 and resulted in cell-cycle block and the induction of apoptosis. When administered orally to in vivo tumor xenograft models, X15695 potently inhibited the growth of breast tumor cells but less efficiently the growth of prostate tumor cells. We therefore identify X15695 as an oral selective ER degrader and propose further development of this compound for therapy of ER+ breast cancers. Significance: An imidazopyridine that selectively degrades ER alpha and is orally bioavailable has been identified for the development of ER+ breast cancer therapeutics. This compound also activates wild-type p53 and disrupts the gain-of-function tumorigenic activity of mutant p53, resulting in cell-cycle arrest and the induction of apoptosis.
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