Beyond small molecules: advancing MYC-targeted cancer therapies through protein engineering

Transcription, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 19

Published: Jan. 29, 2025

Protein engineering has emerged as a powerful approach toward the development of novel therapeutics targeting MYC/MAX/E-box network, an active driver >70% cancers. The MYC/MAX heterodimer regulates numerous genes in our cells by binding Enhancer box (E-box) DNA site and activating transcription downstream genes. Traditional small molecules that inhibit MYC face significant limitations include toxic effects, drug delivery challenges, resistance. Recent advances protein offer promising alternatives creating protein-based drugs directly disrupt dimerization interface and/or MYC/MAX's to specific targets. Designed proteins like Omomyc, DuoMyc, ME47, MEF, Mad activity through dimerization, sequestration, DNA-binding mechanisms. Compared molecules, these engineered can superior specificity efficacy provide potential pathway for overcoming traditional cancer therapies. success highlights importance developing treatments.

Language: Английский

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MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 21, 2024

Abstract RAS and MYC rank amongst the most commonly altered oncogenes in cancer, with being frequently mutated amplified. The cooperative interplay between constitutes a complex multifaceted phenomenon, profoundly influencing tumor development. Together individually, these two regulate most, if not all, hallmarks of including cell death escape, replicative immortality, tumor-associated angiogenesis, invasion metastasis, metabolic adaptation, immune evasion. Due to their frequent alteration role tumorigenesis, emerge as highly appealing targets cancer therapy. However, due nature, both have been long considered “undruggable” and, until recently, no drugs directly targeting them had reached clinic. This review aims shed light on partnership, special attention active collaboration fostering an immunosuppressive milieu driving immunotherapeutic resistance cancer. Within this review, we also present update different inhibitors currently undergoing clinical trials, along outcomes combination strategies explored overcome drug resistance. recent development suggests paradigm shift long-standing belief “undruggability”, hinting at new era therapeutic targeting.

Language: Английский

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Defeating MYC with drug combinations or dual-targeting drugs

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 45(6), P. 490 - 502

Published: May 22, 2024

Language: Английский

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Genomic Landscape of Breast Cancer: Study Across Diverse Ethnic Groups

Diseases, Journal Year: 2025, Volume and Issue: 13(3), P. 86 - 86

Published: March 17, 2025

Background: Breast cancer (BC) is the most common among women worldwide, with incidence and mortality rates varying across ethnic groups due to sociodemographic, clinicopathological, genomic differences. This study aimed characterize landscape of BC in diverse using computational tools explore these variations. Methodology: cBioPortal was used analyze genomic, sociodemographic data from 1084 samples. Mutated genes were classified based on GeneCards platform data. Enrichment analysis performed CancerHallmarks, not found compared MSigDB’s Hallmark Gene Sets. Genes absent both further analyzed NDEx through Cytoscape.org their role cancer. Results: Significant differences (p < 0.05) observed sex, tumor subtypes, genetic ancestry, median fraction altered genome, mutation count, frequencies groups. We identified frequently mutated genes. Some be associated classic hallmarks, such as replicative immortality, sustained proliferative signaling, evasion growth suppressors. However, exact some remains unclear, highlighting need for research better understand involvement biology. Conclusions: significant clinicopathological variations While key hallmarks found, incomplete characterization highlights research, especially focusing groups, biology improve personalized treatments.

Language: Английский

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Rethinking MYC inhibition: a multi-dimensional approach to overcome cancer’s master regulator

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: April 29, 2025

MYC, a master regulator in oncogenesis, has long been deemed "undruggable" due to its intrinsically disordered structure. However, recent advances are overturning this view, with direct inhibitors like Omomyc (OMO-103) and PROTAC-based degraders such as WBC100 showing promising clinical progress. Complementary strategies-including BET CDK9 inhibitors, RNA-based therapeutics, nanobodies, engineered proteases-are expanding the therapeutic landscape. Despite challenges specificity, toxicity, delivery, these innovations underscore MYC's emerging druggability. Moreover, combination therapies integrating MYC chemotherapy, radiotherapy, or immunotherapy demonstrate synergistic potential. This article advocates for multi-dimensional, biomarker-guided approach targeting, emphasizing rational drug combinations continued innovation overcome resistance improve outcomes MYC-driven cancers.

Language: Английский

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Key breakthroughs in small molecule MYC inhibitors

Future Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 4

Published: May 12, 2025

Language: Английский

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Cohesin — bridging the gap among gene transcription, genome stability, and human diseases

FEBS Letters, Journal Year: 2024, Volume and Issue: unknown

Published: June 9, 2024

The intricate landscape of cellular processes governing gene transcription, chromatin organization, and genome stability is a fascinating field study. A key player in maintaining this delicate equilibrium the cohesin complex, molecular machine with multifaceted roles. This review presents an in‐depth exploration these connections their significant impact on various human diseases.

Language: Английский

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L3MBTL2 maintains MYCN‐amplified neuroblastoma cell proliferation through silencing NRIP3 and BRME1 genes

Genes to Cells, Journal Year: 2024, Volume and Issue: 29(10), P. 838 - 853

Published: Aug. 27, 2024

Epigenetic alterations critically affect tumor development. Polycomb-group complexes constitute an evolutionarily conserved epigenetic machinery that regulates stem cell fate and They are implicated in tumorigenesis, primarily via histone modification. Polycomb repressive complex 1 (PRC1) 1-6 (PRC1.1-6) mediate the ubiquitination of H2A on lysine 119 (H2AK119ub). Here, we studied functional roles a PRC1.6 molecule, L3MBTL2, neuroblastoma (NB) cells. L3MBTL2-knockout knockdown revealed L3MBTL2 depletion suppressed NB proliferation cell-cycle arrest gamma-H2A.X upregulation. profoundly xenograft formation. Transcriptome analysis cell-cycle-related activated differentiation-related pathways. Break repair meiotic recombinase recruitment factor (BRME1) nuclear receptor interacting protein 3 (NRIP3) were notably de-repressed by L3MBTL2-knockout. The deletion reduced enrichment H2AK119ub PCGF6 at transcriptional start site proximal regions targets. Add-back studies unveiled importance L3MBTL2-BRME1 -NRIP3 axes for proliferation. We further manifested association MYCN with de-repression NRIP3 L3MBTL2-deficient context. Therefore, this study first significance L3MBTL2-mediated gene silencing MYCN-amplified

Language: Английский

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Combinatorial Anti-Cancer Effect of Polypurine Reverse Hoogsteen Hairpins against KRAS and MYC Targeting in Prostate and Pancreatic Cancer Cell Lines

Genes, Journal Year: 2024, Volume and Issue: 15(10), P. 1332 - 1332

Published: Oct. 16, 2024

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DataXflow: Synergizing data-driven modeling with best parameter fit and optimal control – An efficient data analysis for cancer research

Computational and Structural Biotechnology Journal, Journal Year: 2024, Volume and Issue: 23, P. 1755 - 1772

Published: April 8, 2024

Building data-driven models is an effective strategy for information extraction from empirical data. Adapting model parameters specifically to data with a best fitting approach encodes the relevant into mathematical model. Subsequently, optimal control framework extracts most efficient targets steer desired changes via external stimuli. The DataXflow software integrates three pipelines, D2D fitting, solving problems including stimuli and JimenaE providing graphical user interfaces employ other frameworks lowering barriers need of programming skills, simultaneously automating reoccurring modeling tasks. Such tasks include equation generation graph script allowing also systems many agents, like complex gene regulatory networks. A state defined, therapeutic interventions are modeled as exploits model-encoded purposefully by those that effect efficiently. implementation available under https://github.com/MarvelousHopefull/DataXflow.We showcase its application detecting specific drug therapy lung cancer measurement lower proliferation increase apoptosis. By iterative process refining topology model, network tumor generated An in our example reveals inhibition AURKA activation CDH1 target combination. paves way agile interplay between analysis potentially accelerating research identification, even

Language: Английский

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