A Framework for Autonomous AI-Driven Drug Discovery DOI Creative Commons

Douglas W. Selinger,

Tom Wall,

Eleni Stylianou

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

Abstract The exponential increase in biomedical data offers unprecedented opportunities for drug discovery, yet overwhelms traditional analysis methods, limiting the pace of new development. Here we introduce a framework autonomous artificial intelligence (AI)-driven discovery that integrates knowledge graphs with large language models (LLMs). It is capable planning and carrying out automated programs while providing details its research strategy, progress, supporting points, enabling thorough assessment methods findings. At heart this lies “focal graph” - novel construct harnesses centrality algorithms to distill vast, noisy datasets into concise, transparent, data-driven hypotheses. By high-throughput search result interpretation, such could be used execute massive numbers searches, identify patterns across complex, diverse datasets, prioritize actionable hypotheses at scale speed unachievable by human researchers alone. We demonstrate even small- applications approach can yield novel, transparent insights relevant multiple stages process present prototype system autonomously executing multi-step target workflow. focal graph described here, automation it enables, represents promising path forward: towards deeper understanding mechanisms underlying disease true acceleration development therapeutics. Graphical

Language: Английский

Discovery of a Potent and Selective GSPT1 Molecular Glue Degrader for the Treatment of Castration-Resistant Prostate Cancer DOI
Hui Shen, Hongrui Xu,

W. Q. Jin

et al.

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

Published: Jan. 2, 2025

The treatment of castration-resistant prostate cancer (CRPC) remains a significant challenge, necessitating the development new and promising therapeutic strategies. Utilizing molecular glue to degrade previously intractable drivers represents an emerging approach treatment. In this study, we developed novel CRBN-interacting glue, 7d (XYD049), which exhibits potent selective degradation G1 S phase transition 1 (GSPT1), well-known untargetable driver in diverse cells. Importantly, superior efficacy compared (CC-90009) degrading GSPT1 22Rv1 cells with DC50 value 19 nM. It effectively suppresses growth IC50 0.007 ± 0.004 μM demonstrates inhibiting tumor mice. Mechanistically, via GSPT1, downregulates CRPC-related oncogenes cells, including AR, AR-V7, PSA, c-Myc. Thus, our work provides degrader effectiveness targeting Myc-driven CRPC.

Language: Английский

Citations

0
Targeting MYC for the treatment of breast cancer: use of the novel MYC-GSPT1 degrader, GT19630 DOI Creative Commons
Minhong Tang, John Crown, Michael Duffy

et al.

Investigational New Drugs, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Language: Английский

Citations

0
Integrated Computational Analysis Reveals Early Genetic and Epigenetic AML Susceptibility Biomarkers in Benzene-Exposed Workers DOI Open Access
Silvia Vivarelli, Çiğdem Sevim,

Federica Giambò

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1138 - 1138

Published: Jan. 28, 2025

Benzene, a well-known carcinogenic airborne pollutant, poses significant health risks, particularly in industries such as petroleum, shoemaking, and painting. Despite strict regulations, chronic occupational exposure persists, contributing to the onset of acute myeloid leukemia (AML) other malignancies. Benzene’s carcinogenicity stems from its metabolic activation, leading increased oxidative stress, DNA damage, cancer transformation. While toxicity is well-documented, link between genetic epigenetic alterations susceptibility exposed workers remains underexplored. This study aims identify early biomarkers benzene AML risk by analyzing gene expression methylation datasets GEO DataSets, integrated with molecular pathway analyses, well miRNA-target protein-protein network evaluations. multi-approach led identification nine deregulated genes (CRK, CXCR6, GSPT1, KPNA1, MECP2, MELTF, NFKB1, TBC1D7, ZNF331) benzene, NFKB1 showing strong discriminatory potential. Also, dose-dependent changes were observed CXCR6 while selected miRNAs let-7d-5p, miR-126-3p, miR-361-5p emerged key post-transcriptional regulators. Furthermore, functional enrichment linked these immune response, inflammation, cell proliferation, apoptosis pathways. analyses highlighted CRK, central benzene-associated leukemogenesis. Altogether, findings provide novel insights into an biomarker fingerprint for susceptibility, supporting future development biomolecular-based targeted monitoring personalized preventive strategies at-risk workers.

Language: Английский

Citations

0
Design, Synthesis, and Antitumor Activity Study of Novel Potent Gspt1 Degraders DOI
Li Zhang, Ling Wang,

Meijing Deng

et al.

Published: Jan. 1, 2025

Language: Английский

Citations

0
Discovery of a novel molecular glue degrader targeting GSPT1/2 with a non-IMiD based CRBN binder DOI Creative Commons

Seulki Park,

Akshay D. Takwale,

Jieun Lee

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117642 - 117642

Published: April 1, 2025

Targeting undruggable proteins by inducing proximity between E3 ligase and their substrates has emerged as an innovative strategy for tackling challenging diseases. In this study, we identified a novel GSPT1 degrader, 4a (KMG-1068), through screening of our in-house small molecule library. Treatment with demonstrated significant anti-proliferative activity across multiple cell lines, which was diminished co-treatment MLN4924, suggesting the involvement Cullin-containing complex. Quantitative proteomic analysis indicated that predominantly induces degradation GSPT1/2. We further validated 4a-mediated GSPT1/2 is dependent on both CUL4 CRBN. Moreover, forms ternary complex CRBN GSPT1/2, albeit weaker binding affinity compared to reported molecular glues. BRET assays competition pomalidomide binds C-terminal IMiD site CRBN, leading GSPT1. Despite lacking characteristic glutarimide moiety present in other CRBN-based glue degraders, interacts effectively Structural characterization analog synthesis underscored importance specific structural features engagement, degradation, effects, establishing promising degrader therapeutic potential.

Language: Английский

Citations

0
A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer DOI Creative Commons

Prachi Walke,

Jared D.W. Price,

Frederick S. Vizeacoumar

et al.

Oncogene, Journal Year: 2025, Volume and Issue: unknown

Published: April 29, 2025

Language: Английский

Citations

0
A Dual-Target and Dual-Mechanism Design Strategy by Combining Inhibition and Degradation Together DOI
Y.-C. Liu, Xiuyun Sun,

Qianlong Liu

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 2, 2024

Glioblastoma, a highly aggressive brain tumor, lacks effective treatment with low 5 year survival rates. Urgency for new therapies is evident. Mammalian targets of rapamycin (mTOR) and G1 to S phase transition 1 gene (GSPT1) are overexpressed in glioblastoma, regulating vital cellular functions. Current mTOR inhibitors face challenges clinical efficacy drug resistance. Similarly, GSPT1-targeting have not progressed glioblastoma trials. Research studies suggested that combining inhibition GSPT1 degradation may overcome resistance enhance efficacy. We propose the concept jointly implementing on different proteins, integrating properties degraders into same molecule. Introducing YB-3–17, novel bifunctional molecule, robustly inhibits selectively degrades GSPT1. As tool compound proof-of-concept studies, YB-3–17 sharpens selectivity, avoiding off-target effects, induces inhibition, showing superior tumor cell lines compared standalone therapies. RNA-seq analysis highlights advantages YB-3-17 over inhibitor treatment. can safely effectively inhibit growth mice, offering promising direction precision representing first attempt combine degradation. This work also demonstrates it conceptually possible successfully small molecule single killing two birds one stone.

Language: Английский

Citations

3
Rational Design of Dual Degraders by Incorporating Molecular Glue Structural Features into PROTAC Degraders DOI
Bowen Zhang, Shan Gao,

Ting-Ting Wu

et al.

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

Published: May 9, 2025

PROTAC and molecular glue present a novel therapeutic approach to tackle diseases propelled by the aberrant expression of disease-causing proteins. In this study, we identified number AR/AR-V7 GSPT1 degraders that possess both characteristics. The exploration SAR led discovery BWA-6047 as potent degrader. exhibited protein degradation in 22Rv1 cells (AR: DC50 = 3.7 nM, Dmax 90%; AR-V7: 3.0 93%; GSPT1: 1.2 94%). Mechanism experiments indicate functions degrade target Oral administration at 20 mpk significantly inhibited LNCaP xenograft tumor growth mice without obvious toxicity. Dual represent class promising mechanism compounds for further extensive evaluations prostate cancer treatment.

Language: Английский

Citations

0
Development and therapeutic potential of GSPT1 molecular glue degraders: A medicinal chemistry perspective DOI

Xiujin Chang,

Fangui Qu,

Chunxiao Li

et al.

Medicinal Research Reviews, Journal Year: 2024, Volume and Issue: 44(4), P. 1727 - 1767

Published: Feb. 5, 2024

Abstract Unprecedented therapeutic targeting of previously undruggable proteins has now been achieved by molecular‐glue‐mediated proximity‐induced degradation. As a small GTPase, G1 to S phase transition 1 (GSPT1) interacts with eRF1, the translation termination factor, facilitate process termination. Studied demonstrated that GSPT1 plays vital role in acute myeloid leukemia (AML) and MYC‐driven lung cancer. Thus, molecular glue (MG) degraders is novel promising approach for treating AML cancers. In this Perspective, we briefly summarize structural functional aspects GSPT1, highlighting latest advances challenges MG degraders, as well some representative patents. The structure‐activity relationships, mechanism action pharmacokinetic features are emphasized provide comprehensive compendium on rational design degraders. We hope an updated overview, guide strategies treatment

Language: Английский

Citations

2
Role of Proteins in Oncology: Advances in Cancer Diagnosis, Prognosis, and Targeted Therapy—A Narrative Review DOI Open Access
Magdalena Kędzierska,

Magdalena Bańkosz

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(23), P. 7131 - 7131

Published: Nov. 25, 2024

Modern oncology increasingly relies on the role of proteins as key components in cancer diagnosis, prognosis, and targeted therapy. This review examines advancements protein biomarkers across several types, including breast cancer, lung ovarian hepatocellular carcinoma. These have proven critical for early detection, treatment response monitoring, tailoring personalized therapeutic strategies. The article highlights utility therapies, such tyrosine kinase inhibitors monoclonal antibodies, improving efficacy while minimizing systemic toxicity. Despite these advancements, challenges like tumor resistance, variability expression, diagnostic heterogeneity persist, complicating universal application. underscores future directions, integration artificial intelligence, advanced analysis technologies, development combination therapies to overcome barriers refine treatment.

Language: Английский

Citations

2