Abstract
Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa). Although most patients initially respond to ADT, almost all cancers eventually develop castration resistance. Castration-resistant PCa (CRPC) is associated with a very poor prognosis, and the treatment of which is a serious clinical challenge. Accumulating evidence suggests that abnormal expression and activation of various kinases are associated with the emergence and maintenance of CRPC. Many efforts have been made to develop small molecule inhibitors to target the key kinases in CRPC. These inhibitors are designed to suppress the kinase activity or interrupt kinase-mediated signal pathways that are associated with PCa androgen-independent (AI) growth and CRPC development. In this review, we briefly summarize the roles of the kinases that are abnormally expressed and/or activated in CRPC and the recent advances in the development of small molecule inhibitors that target kinases for the treatment of CRPC.
Highlights
Introduction tral with regard to jurisdictionalKinases are part of the large family of phosphotransferase, which catalyze the transfer of a phosphate moiety from a high energy molecule to their substrate molecule
Many small molecule inhibitors have been developed to or mainly target the key kinases involved in Castration-resistant PCa (CRPC) emergence and maintenance, some of them have been approved by U.S Food and Drug Administration (FDA) [11,12]
riboflavin kinases (RFK) catalyzes the phosphorylation of riboflavin to create flavin mononucleotide (FMN), which is an important cofactor and a precursor to flavin adenine dinucleotide (FAD) as well as a redox cofactor used by many enzymes in metabolism
Summary
Kinases are part of the large family of phosphotransferase, which catalyze the transfer of a phosphate moiety from a high energy molecule (such as ATP) to their substrate molecule. Many small molecule inhibitors have been developed to or mainly target the key kinases involved in CRPC emergence and maintenance, some of them have been approved by U.S Food and Drug Administration (FDA) [11,12] These small molecules are designed to inhibit kinase activity or interrupt kinase-mediated signal pathways that are associated with PCa androgen-independent (AI) growth, progression, and metastasis (Figures 1 and 2, Table 1). Some of these kinase inhibitors have been applied in clinical trials (Table 2). MTORC1-S6K1 translation signaling and sequentially block anti-apoptotic protein MCL-l synthesis [48]
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