Role of bromodomain and extraterminal (BET) proteins in prostate cancer

Expert Opinion on Investigational Drugs, Journal Year: 2023, Volume and Issue: 32(3), P. 213 - 228

Published: March 1, 2023

Introduction The bromodomain and extraterminal (BET) family of proteins are epigenetic readers acetylated histones critical activators oncogenic networks across many cancers. Therapeutic targeting BET has been an attractive area clinical development for metastatic castration-resistant prostate cancer. In recent years, structurally diverse inhibitors have discovered tested. Preclinical studies demonstrated significant antiproliferative activity against However, their success as monotherapies limited by treatment-associated toxicities, primary acquired drug resistance, a lack predictive biomarkers benefit.Areas covered This review provides overview advancements in inhibitor design, preclinical research, conclusions from trials We speculate on incorporating into combination regimens with other agents to improve the therapeutic index inhibition treating cancer.Expert opinion potential cancer studies. further research is needed identify that can predict sensitivity develop novel, highly selective reduce toxicities. Finally, likely hold most agents.

Language: Английский

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When Just One Phosphate Is One Too Many: The Multifaceted Interplay between Myc and Kinases

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4746 - 4746

Published: March 1, 2023

Myc transcription factors are key regulators of many cellular processes, with target genes crucially implicated in the management cell proliferation and stem pluripotency, energy metabolism, protein synthesis, angiogenesis, DNA damage response, apoptosis. Given wide involvement dynamics, it is not surprising that its overexpression frequently associated cancer. Noteworthy, cancer cells where high levels maintained, Myc-associated kinases often observed required to foster tumour cells’ proliferation. A mutual interplay exists between kinases: latter, which transcriptional targets, phosphorylate Myc, allowing activity, highlighting a clear regulatory loop. At level, activity turnover also tightly regulated by kinases, finely tuned balance translation rapid degradation. In this perspective, we focus on cross-regulation underlying similar redundant mechanisms regulation at different levels, from post-translational events. Furthermore, review indirect effects known kinase inhibitors provides an opportunity identify alternative combined therapeutic approaches for treatment.

Language: Английский

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Rational design, synthesis and biological evaluation of benzo[d]isoxazole derivatives as potent BET bivalent inhibitors for potential treatment of prostate cancer

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 135, P. 106495 - 106495

Published: March 28, 2023

Language: Английский

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Synthesis, Biochemical Characterization, and Genetic Encoding of a 1,2,4‐Triazole Amino Acid as an Acetyllysine Mimic for Bromodomains of the BET Family

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 62(12)

Published: Dec. 31, 2022

Abstract Lysine acetylation is a charge‐neutralizing post‐translational modification of proteins bound by bromodomains (Brds). A 1,2,4‐triazole amino acid (ApmTri) was established as acetyllysine (Kac) mimic recruiting Brds the BET family in contrast to glutamine commonly used for simulating this modification. Optimization triazole substituents and side chain spacing allowed Brd recruitment ApmTri‐containing peptides with affinities similar native substrates. Crystal structures complex two revealed binding mode which mirrored that Kac ligands. ApmTri genetically encoded recombinant co‐enriched BRD3(2) from cellular lysates. This interaction blocked inhibitor JQ1. With ApmTri, biochemistry now provided stable reflecting charge neutralization recruitment, allowing new investigations into vitro vivo.

Language: Английский

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Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 22, 2024

Abstract Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women advanced TNBC exhibit aggressive disease have limited treatment options. Although TME implicated in driving of basal/TNBC therapy resistance, effectively targeting it remains a challenge. Minnelide, prodrug triptolide currently being tested clinical trials, has shown anti-tumorigenic activity multiple malignancies via super enhancers, Myc anti-apoptotic pathways such as HSP70. Distinct super-enhancer landscape drives stem cells (CSC) while inducing TME. We show that Minnelide selectively targets CSCs human murine cell lines compared to luminal by combination cyclophosphamide significantly reduces the growth eliminates metastasis reprogramming enhancing cytotoxic T infiltration 4T1 tumor-bearing mice. Resection residual tumors following leads complete eradication disseminated all mice are free local distant recurrences. All control showed recurrences within 3 weeks post-resection single delayed recurrence one mouse was tumor. provide evidence intrinsic reprograms microenvironment. Our studies also suggest may lead durable responses patients warranting its investigation.

Language: Английский

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