Yu, Jiang published the artcileDiscovery and biological evaluation of darolutamide derivatives as inhibitors and down-regulators of wild-type AR and the mutants, Product Details of C10H6ClN3, the publication is European Journal of Medicinal Chemistry (2019), 111608, database is CAplus and MEDLINE.
Androgen receptor (AR) has been a target of prostate cancer (PC) for nearly six decades. Recently, down-regulating or degrading AR and the mutants especially the splice variant 7 (AR-V7) lacking ligand binding domain (LBD) emerged as an advantageous therapeutic approach to overcome drug resistance. Here, the structural modification of darolutamide resulted in the discovery of dual-action AR inhibitors and down-regulators. Unlike other traditional AR antagonists targeting the AR-LBD, compounds 4k and 4b not only inhibit the activities of wt-AR and AR-F876L mutant but also down-regulate the protein expression of full-length (AR-full) and AR variant 7 (AR-V7) at mRNA level. In cell proliferation assays, compounds 4k and 4b exhibited better antiproliferative activities than darolutamide and enzalutamide against AR-V7-pos. 22Rv1 cells and VCaP cells. In addition, 4k demonstrated better antitumor activity than clin. used enzalutamide in castration-resistant VCaP xenograft model. Collectively, combining the activities of AR inhibition and down-regulation, compound 4k is proposed as an advantageous lead compound to disrupt AR signaling and overcome resistance.
European Journal of Medicinal Chemistry published new progress about 1297537-37-1. 1297537-37-1 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Chloride,Nitrile,Benzene, name is 2-Chloro-4-(1H-pyrazol-5-yl)benzonitrile, and the molecular formula is C14H20BNO3, Product Details of C10H6ClN3.
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