B cell receptor (BCR) signaling plays a key role in B cell development and function. Aberrant BCR signaling has been confirmed as a central driver for the pathogenesis of various B cell malignancies. Bruton's tyrosine kinase (BTK) is a vital component of BCR signaling and exhibits overexpression in various B cell leukemias and lymphomas. Inhibiting BTK has been proved as an efficient way for B cell malignancy intervention. Remarkable achievements have been made in the pursuit of selective BTK inhibitors, represented by the success of the irreversible BTK inhibitors, ibrutinib and acalabrutinib. Constantly emerging agents exhibiting superior efficacy and safety in preclinical and clinical studies provide promising therapeutics for the treatment of B cell malignancies.
The androgen receptor (AR), a ligand-dependent transcription factor that regulates the expression of a series of downstream target genes after the binding of androgens, has been a target for the discovery of drugs used to treat prostate cancer. Prostate cancer always progresses to castration-resistant prostate cancer after a period of androgen deprivation therapy. Thus, developing potent androgen receptor antagonists for the therapy of castration-resistant prostate cancer possesses great significance. This review summarizes the preclinical development of androgen receptor antagonists, conventional androgen receptor antagonists that competitively bind to the ligand binding domain of the androgen receptor and coactivator antagonists of the androgen receptor, including both activation function-2 antagonists and binding function-3 antagonists. We hope that this review can help other researchers find new scaffolds and sites for the treatment of prostate cancer.
The natural products piperlongumine (1) and ligustrazine (2) have been reported to exert antiproliferative effects against various types of cancer cells by up-regulating the level of reactive oxidative species (ROS). However, the moderate activities of 1 and 2 limit their application. To improve their potential antitumor activity, novel piperlongumine/ligustrazine derivatives were designed and prepared, and their potential pharmacological effects were determined in vitro and in vivo. Among the derivatives obtained, 11 exerted more prominent inhibitory activities against proliferation of drug-sensitive/-resistant cancer cells with lower IC 50 values than 1. Particularly, the IC 50 value of 11 against drug-resistant Bel-7402/5-FU cells was 0.9 μM, which was about 9-fold better than that of 1 (IC 50 value of 8.4 μM). Mechanistic studies showed that 11 demonstrated thioredoxin reductase (TrxR) inhibitory activity, increase of ROS levels, decrease of mitochondrial transmembrane potential levels, and occurrence of DNA damage and autophagy, in a dose-dependent manner, via regulation of DNA damage protein H2AX and autophagy-associated proteins LC3, beclin-1, and p62 in drug-resistant Bel-7402/5-FU cells. Finally, compound 11 at 5 mg/kg displayed potent antitumor activity in vivo with tumor suppression of 76% (w/w). Taken together, compound 11 may represent a promising candidate drug for the chemotherapy of drug-resistant hepatocellular carcinoma and warrant more intensive study.
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