Characterization of preclinical radio ADME properties of ARV-471 for predicting human PK using PBPK modeling DOI Creative Commons
Yifei He,

Chenggu Zhu,

Lei Peng

et al.

Journal of Pharmaceutical Analysis, Journal Year: 2024, Volume and Issue: unknown, P. 101175 - 101175

Published: Dec. 1, 2024

Language: Английский

PROTACs coupled with oligonucleotides to tackle the undruggable DOI
Guangshuai Zhang,

Si Yan,

Yan Liu

et al.

Bioanalysis, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 16

Published: Feb. 3, 2025

Undruggable targets account for roughly 85% of human disease-related and represent a category therapeutic that are difficult to tackle with traditional methods, but their considerable clinical importance. These generally defined by planar functional interfaces the absence efficient ligand-binding pockets, making them unattainable conventional pharmaceutical strategies. The advent oligonucleotide-based proteolysis-targeting chimeras (PROTACs) has instilled renewed optimism in addressing these challenges. PROTACs facilitate targeted degradation undruggable entities, including transcription factors (TFs) RNA-binding proteins (RBPs), via proteasome-dependent mechanisms, thereby presenting novel approaches diseases linked targets. This review offers an in-depth examination recent progress integration PROTAC technology oligonucleotides target traditionally proteins, emphasizing design principles mechanisms action innovative PROTACs.

Language: Английский

Citations

2
Overcoming drug resistance in castrate-resistant prostate cancer: current mechanisms and emerging therapeutic approaches DOI Open Access
Adam Khorasanchi, Feng Hong, Yuanquan Yang

et al.

Cancer Drug Resistance, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Metastatic castration-resistant prostate cancer (mCRPC) is driven by a complex network of resistance mechanisms against standard-of-care therapies, resulting in poor long-term outcomes. This review offers uniquely comprehensive and integrative perspective on these pathways, systematically examining both androgen receptor (AR)-dependent factors (including AR overexpression, point mutations, glucocorticoid signaling, splice variants, post-translational modifications, altered coregulators, intratumoral hormone biosynthesis) AR-independent pathways (such as neuroendocrine differentiation, lineage plasticity, alternative growth factor signaling). We also highlight influencing immunotherapy, chemotherapy, radiopharmaceutical therapy targeted therapy. By synthesizing emerging insights across domains, this not only clarifies the underlying biology mCRPC but identifies key leverage points for more effective interventions. Building foundation, we propose forward-looking framework overcoming drug resistance, emphasizing importance biomarker-guided patient selection, combination strategies that simultaneously target multiple mechanisms, novel therapies under investigation. These recommendations are intended to guide future clinical trial designs research priorities move beyond incremental improvements. Ultimately, synthesis aims serve resource clinicians researchers accelerate development durable, precision-based treatment mCRPC.

Language: Английский

Citations

2
Overcoming cancer therapy resistance: From drug innovation to therapeutics DOI

Jinrui Wei,

Meng‐Yi Lu,

Tian‐Hua Wei

et al.

Drug Resistance Updates, Journal Year: 2025, Volume and Issue: 81, P. 101229 - 101229

Published: March 8, 2025

Language: Английский

Citations

2
Discovery of the First Potent ROR1 Degrader for the Treatment of Non-Small Cell Lung Cancer DOI
Jinlin Li,

Lin Li,

Hou Cai-yun

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117325 - 117325

Published: Jan. 1, 2025

Language: Английский

Citations

1
Interplay of PROTAC Complex Dynamics for Undruggable Targets: Insights into Ternary Complex Behavior and Linker Design DOI
Harish Kumar,

M. Elizabeth Sobhia

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(8), P. 1306 - 1318

Published: July 29, 2024

Protein degraders, such as bifunctional proteolysis-targeting chimeras (PROTACs), selectively eliminate target proteins by leveraging the natural protein degradation machinery. PROTACs bridge with an E3 ligase, which induces ubiquitination and degradation. Investigating ternary complex structures elucidates molecular mechanisms of their formation This study examines binding dynamics ligases (VHL, CRBN, cIAP) interest, focusing on dynamics, cooperativity, selectivity, linker length, PROTAC conformations. The influence interface residues lengths specific conformations for is highlighted. Utilizing steered simulations, provides comprehensive parameters behavior stability diverse complexes. These insights are crucial designing targeting disease-causing advancing development degradable complexes therapeutic applications.

Language: Английский

Citations

6
Transforming Therapeutic Approaches with PROTAC Technology: New Targets and Potentials DOI Creative Commons
Robert B. Kargbo

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(5), P. 573 - 575

Published: April 26, 2024

This Patent Highlight delves into the ground-breaking impact of Proteolysis Targeting Chimeras (PROTACs) on targeted protein degradation, offering novel strategies to eliminate pathogenic proteins. By exploring cutting-edge development compounds targeting IRAK-4 and CDK2, this work illuminates PROTACs' role in treating immune disorders cancer. The analysis not only highlights specificity potential PROTACs transforming disease treatment but also addresses challenges future directions technology, emphasizing its broad applicability promise more effective therapeutic strategies.

Language: Английский

Citations

3
HDAC-driven mechanisms in anticancer resistance: epigenetics and beyond DOI Open Access

Martina Minisini,

Massimo Mascaro,

Claudio Brancolini

et al.

Cancer Drug Resistance, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 20, 2024

The emergence of drug resistance leading to cancer recurrence is one the challenges in treatment patients. Several mechanisms can lead resistance, including epigenetic changes. Histone deacetylases (HDACs) play a key role chromatin regulation through and are also involved resistance. control histone acetylation accessibility regulatory DNA sequences such as promoters, enhancers, super-enhancers known by which HDACs influence gene expression. Other targets that not histones contribute This review describes contribution that, some cases, may determine chemotherapy or other treatments.

Language: Английский

Citations

3
EGFR molecular degraders: preclinical successes and the road ahead DOI Creative Commons

Naveen Chand Rallabandi,

Dayanand Panpatil,

Digvijay Gahtory

et al.

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

Published: Feb. 10, 2025

Language: Английский

Citations

0
Computational approaches to aid PROTAC drug discovery DOI

Sohini Chakraborti,

Kirsten McAulay

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Targeting Oncogenic Pathways: Advances in KRAS, CDK, EGFR, and PROTAC-Based Therapies DOI Creative Commons
Robert B. Kargbo

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: 16(4), P. 523 - 525

Published: March 11, 2025

Recent advancements in cancer therapy focus on targeting critical mutations and regulatory pathways, particularly KRAS cyclin-dependent kinases (CDKs), which drive progression. This Patent Highlight showcases the development of novel small-molecule inhibitors for CDKs, highlighting their mechanisms action, findings from preclinical studies, potential improving therapeutic outcomes cancers such as nonsmall cell lung (NSCLC), colorectal, pancreatic cancers.

Language: Английский

Citations

0