Targeting Protein Kinases and Epigenetic Control as Combinatorial Therapy Options for Advanced Prostate Cancer Treatment

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Abstract

Prostate cancer (PC), the fifth leading cause of cancer-related mortality worldwide, is known as metastatic bone cancer when it spreads to the bone. Although there is still no effective treatment for advanced/metastatic PC, awareness of the molecular events that contribute to PC progression has opened up opportunities and raised hopes for the development of new treatment strategies. Androgen deprivation and androgen-receptor-targeting therapies are two gold standard treatments for metastatic PC. However, acquired resistance to these treatments is a crucial challenge. Due to the role of protein kinases (PKs) in the growth, proliferation, and metastases of prostatic tumors, combinatorial therapy by PK inhibitors may help pave the way for metastatic PC treatment. Additionally, PC is known to have epigenetic involvement. Thus, understanding epigenetic pathways can help adopt another combinatorial treatment strategy. In this study, we reviewed the PKs that promote PC to advanced stages. We also summarized some PK inhibitors that may be used to treat advanced PC and we discussed the importance of epigenetic control in this cancer. We hope the information presented in this article will contribute to finding an effective treatment for the management of advanced PC.

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VMD: Visual molecular dynamics

William Humphrey, Andrew Dalke, Klaus Schulten (1996)

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The protein kinase complement of the human genome.

G. Manning (2002)

We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.

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Natural products in drug discovery: advances and opportunities

Atanas Atanasov, Sergey B. Zotchev, Verena Dirsch … (2021)

Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities.