Multi-Water Bridges Enable Design of BET BD1-Selective Inhibitors for Pancreatic Cancer Therapy DOI
Xuetao Chen,

Wenjing Kang,

Tingting Wu

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Rational design of bromodomain (BD)-selective inhibitors could mitigate on-target toxicities associated with pan-BET inhibition but is challenging despite the availability high-resolution structures. By simultaneously forming water bridges BD1-specific residues in both BC ring and ZA channel, we identified a potent orally bioavailable BET BD1-selective inhibitor DDO-8958, which exhibited KD 5.6 nM for BRD4 BD1 214-fold selectivity over BD2. The cocrystal structure demonstrated unique multi-water bridge mechanism involving K91- D145-driven selectivity. DDO-8958 extensively influenced oncogene expression metabolic pathway, including oxidative phosphorylation MIA PaCa-2. In vivo, inhibited tumor growth markedly augmented therapeutic efficacy glycolysis 2-DG. These findings illuminate that enable strategy combined targeting BD1-induced epigenetic reprogramming pathways management pancreatic cancer.

Language: Английский

Molecular hybridization: a powerful tool for multitarget drug discovery DOI
Pedro de Sena Murteira Pinheiro, Lucas Silva Franco, Tadeu L. Montagnoli

et al.

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(4), P. 451 - 470

Published: March 8, 2024

Introduction The current drug discovery paradigm of 'one drug, multiple targets' has gained attention from both the academic medicinal chemistry community and pharmaceutical industry. This is in response to urgent need for effective agents treat multifactorial chronic diseases. molecular hybridization strategy a useful tool that been widely explored, particularly last two decades, design multi-target drugs.

Language: Английский

Citations

52
Epigenetics-targeted drugs: current paradigms and future challenges DOI Creative Commons

Wanlin Dai,

Xinbo Qiao, Yuanyuan Fang

et al.

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

Published: Nov. 26, 2024

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone RNA remodeling, and non-coding regulation. These mechanisms their associated enzymes convey genetic information independently of base sequences, playing essential roles in organismal development homeostasis. Conversely, disruptions epigenetic landscapes critically influence the pathogenesis various human diseases. This understanding has laid robust theoretical groundwork for developing drugs that target epigenetics-modifying pathological conditions. Over past two decades, growing array small molecule targeting such as methyltransferase, deacetylase, isocitrate dehydrogenase, enhancer zeste homolog 2, have been thoroughly investigated implemented therapeutic options, particularly oncology. Additionally, numerous epigenetics-targeted are undergoing clinical trials, offering promising prospects benefits. review delineates epigenetics physiological contexts underscores pioneering studies on discovery implementation drugs. include inhibitors, agonists, degraders, multitarget agents, aiming to identify practical challenges avenues future research. Ultimately, this aims deepen epigenetics-oriented strategies further application settings.

Language: Английский

Citations

35
Targeting of TAMs: can we be more clever than cancer cells? DOI Creative Commons
Julia Kzhyshkowska, Jiaxin Shen, Irina Larionova

et al.

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(12), P. 1376 - 1409

Published: Nov. 8, 2024

АBSTRACT: With increasing incidence and geography, cancer is one of the leading causes death, reduced quality life disability worldwide. Principal progress in development new anticancer therapies, improving efficiency immunotherapeutic tools, personification conventional therapies needs to consider cancer-specific patient-specific programming innate immunity. Intratumoral TAMs their precursors, resident macrophages monocytes, are principal regulators tumor progression therapy resistance. Our review summarizes accumulated evidence for subpopulations number biomarkers, indicating predictive value clinical parameters carcinogenesis resistance, with a focus on solid cancers non-infectious etiology. We present state-of-the-art knowledge about tumor-supporting functions at all stages highlight recently identified by single-cell spatial analytical methods, that discriminate between tumor-promoting tumor-inhibiting TAMs, where both subtypes express combination prototype M1 M2 genes. focuses novel mechanisms involved crosstalk among epigenetic, signaling, transcriptional metabolic pathways TAMs. Particular attention has been given link cell metabolism epigenetic histone lactylation, which can be responsible unlimited protumoral Finally, we explain how interfere currently used therapeutics summarize most advanced data from trials, divide into four categories: inhibition TAM survival differentiation, monocyte/TAM recruitment tumors, functional reprogramming genetic enhancement macrophages.

Language: Английский

Citations

25
Consensus, debate, and prospective on pancreatic cancer treatments DOI Creative Commons
Junke Wang, Jie Yang, Amol Narang

et al.

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Oct. 10, 2024

Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite improvement multi-modality treatment strategies, prognosis pancreatic was not improved dramatically. For resectable or borderline patients, surgical strategy centered on improving R0 resection rate is consensus; however, role neoadjuvant therapy in patients and optimal chemotherapy with without radiotherapy were debated. Postoperative adjuvant gemcitabine/capecitabine mFOLFIRINOX recommended regardless margin status. Chemotherapy as first-line for advanced metastatic included FOLFIRINOX, gemcitabine/nab-paclitaxel, NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan only standard care second-line therapy. Immunotherapy an innovative although anti-PD-1 antibody currently agent approved by MSI-H, dMMR, TMB-high tumors, which represent very small subset cancers. Combination strategies to increase immunogenicity overcome immunosuppressive tumor microenvironment may sensitize immunotherapy. Targeted therapies represented PARP KRAS inhibitors are also under investigation, showing benefits progression-free survival objective response rate. This review discusses current modalities highlights cancer.

Language: Английский

Citations

22
Epigenetic modulations in triple-negative breast cancer: Therapeutic implications for tumor microenvironment DOI Creative Commons
Linlin Zhou, Danny Yu

Pharmacological Research, Journal Year: 2024, Volume and Issue: 204, P. 107205 - 107205

Published: May 6, 2024

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen receptors, progesterone receptors and lacks HER2 overexpression. This absence of critical molecular targets poses significant challenges for conventional therapies. Immunotherapy, remarkably immune checkpoint blockade, offers promise TNBC treatment, but its efficacy remains limited. Epigenetic dysregulation, including altered DNA methylation, histone modifications, imbalances in regulators such as BET proteins, plays a crucial role development resistance to treatment. Hypermethylation tumor suppressor gene promoters the imbalance methyltransferases EZH2 deacetylases (HDACs) profoundly influence cell proliferation, survival, metastasis. In addition, epigenetic alterations critically shape microenvironment (TME), composition, cytokine signaling, expression, ultimately contributing evasion. Targeting these mechanisms with specific inhibitors HDAC combination immunotherapy represents compelling strategy remodel TME, potentially overcoming evasion enhancing therapeutic outcomes TNBC. review aims comprehensively elucidate current understanding modulation TNBC, on potential combining therapies overcome posed by this subtype.

Language: Английский

Citations

17
Prostate cancer epigenetics — from pathophysiology to clinical application DOI
Vera Constâncio, João Lobo, José Pedro Sequeira

et al.

Nature Reviews Urology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

Language: Английский

Citations

2
SMARCA2 protein: structure, function and perspectives of drug design DOI

Zhaolin Guo,

Peng Wang, Yuxuan Han

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117319 - 117319

Published: Jan. 1, 2025

Language: Английский

Citations

2
Advances in Host–Pathogen Interactions in Tuberculosis: Emerging Strategies for Therapeutic Intervention DOI Open Access
Mohammad Javad Nasiri, Vishwanath Venketaraman

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1621 - 1621

Published: Feb. 14, 2025

Tuberculosis (TB) remains one of the most challenging infectious diseases, with Mycobacterium tuberculosis (Mtb) employing sophisticated mechanisms to evade host immunity and establish persistent infections. This review explores recent advances in understanding Mtb's immune evasion strategies; granuloma dynamics; emerging immunotherapeutic approaches. Key findings highlight manipulation autophagy; metabolic reprogramming; cytokine pathways by Mtb sustain its survival within cells. Insights into formation reveal critical role bacterial lipids; modulation; hypoxia-driven dormancy maintaining chronic infection. Innovative therapeutic strategies, including host-directed therapies; epigenetic interventions; immunomodulators, hold promise for improving TB management combating drug-resistant strains. Despite these advancements, significant challenges remain, development effective vaccines; addressing latent TB; ensuring equitable access novel treatments. The integration advanced technologies such as artificial intelligence multi-omics approaches, alongside global collaboration, is essential overcome hurdles. underscores importance a multidisciplinary approach tackling TB, ultimate goal eradicating this health threat.

Language: Английский

Citations

2
Breaking the Barrier: Epigenetic Strategies to Combat Platinum Resistance in Colorectal Cancer DOI Creative Commons

Shiwen Luo,

Yue Ming, Dequan Wang

et al.

Drug Resistance Updates, Journal Year: 2024, Volume and Issue: 77, P. 101152 - 101152

Published: Sept. 28, 2024

Language: Английский

Citations

9
PROTAC technology for prostate cancer treatment DOI Creative Commons
Zhen Wang, Dingpeng Zhang, Hiroyuki Inuzuka

et al.

Acta Materia Medica, Journal Year: 2025, Volume and Issue: 4(1)

Published: Jan. 1, 2025

Prostate cancer (PrCa) is the most prevalent urogenital affecting men. PrCa marked by uncontrolled cellular growth that leads to abnormal enlargement of prostate gland. The metastatic spread primary cause mortality, causing cell dissemination distant sites, such as bones, pelvis, and various visceral organs. Key contributors progression include genetic mutations, elevated androgen receptor expression, gene amplification, rise splice variants. Although deprivation therapy remains mainstay for early-stage treatment, efficacy temporary because many cases advance castration-resistant (CRPC), presenting a significant therapeutic hurdle. This review explores key biomarkers latest strategies CRPC with particular focus on innovative proteolysis-targeting chimera (PROTAC) technology. approach offers novel means degrading target proteins we discuss how PROTAC holds potential effective combat resistance mechanisms in CRPC.

Language: Английский

Citations

1