59736-34-4Relevant articles and documents
Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer
Endo, Satoshi,Oguri, Hiroaki,Segawa, Jin,Kawai, Mina,Hu, Dawei,Xia, Shuang,Okada, Takuya,Irie, Katsumasa,Fujii, Shinya,Gouda, Hiroaki,Iguchi, Kazuhiro,Matsukawa, Takuo,Fujimoto, Naohiro,Nakayama, Toshiyuki,Toyooka, Naoki,Matsunaga, Toshiyuki,Ikari, Akira
, p. 10396 - 10411 (2020/11/02)
Aldo-keto reductase (AKR) 1C3 catalyzes the synthesis of active androgens that promote the progression of prostate cancer. AKR1C3 also contributes to androgen-independent cell proliferation and survival through the metabolism of prostaglandins and reactive aldehydes. Because of its elevation in castration-resistant prostate cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for CRPC. In this study, we found a novel potent AKR1C3 inhibitor, N-(4-fluorophenyl)-8-hydroxy-2-imino-2H-chromene-3-carboxamide (2d), and synthesized its derivatives with IC50 values of 25-56 nM and >220-fold selectivity over other AKRs (1C1, 1C2, and 1C4). The structural factors for the inhibitory potency were elucidated by crystallographic study of AKR1C3 complexes with 2j and 2l. The inhibitors suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through both androgen-dependent and androgen-independent mechanisms. Additionally, 2j and 2l prevented prostate tumor growth in a xenograft mouse model. Furthermore, the inhibitors significantly augmented apoptotic cell death induced by anti-CRPC drugs (abiraterone or enzalutamide).
SUBSTITUTED 2-ACYLAMINO-CYCLOAKYLTHIOPHENE-3-CARBOXYLIC ACID ARYLAMIDES AS INHIBITORS OF CALCIUM-ACTIVATED CHLORIDE CHANNEL TMEM16A
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Page/Page column 19; 30, (2018/11/22)
Provided herein are inhibitors of transmembrane protein 16A (TMEM 16A), a Ca2+-activated CI" channel expressed widely in mammalian epithelia, as well as in vascular smooth muscle and some tumors and electrically excitable cells. TMEM16A inhibit
Low molecular weight amidoximes that act as potent inhibitors of lysine-specific demethylase 1
Hazeldine, Stuart,Pachaiyappan, Boobalan,Steinbergs, Nora,Nowotarski, Shannon,Hanson, Allison S.,Casero, Robert A.,Woster, Patrick M.
, p. 7378 - 7391 (2012/10/29)
The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 dysregulation is thought to contribute to the development of cancer. We reported that (bis)guanidines, (bis)biguanides, and their urea- and thiourea isosteres are potent inhibitors of LSD1 and induce the re-expression of aberrantly silenced tumor suppressor genes in tumor cells in vitro. We now report a series of small molecule amidoximes that are moderate inhibitors of recombinant LSD1 but that produce dramatic changes in methylation at the histone 3 lysine 4 (H3K4) chromatin mark, a specific target of LSD1, in Calu-6 lung carcinoma cells. In addition, these analogues increase cellular levels of secreted frizzle-related protein (SFRP) 2, H-cadherin (HCAD), and the transcription factor GATA4. These compounds represent leads for an important new series of drug-like epigenetic modulators with the potential for use as antitumor agents.