Discovery of Alkenyl Oxindole as a Novel PROTAC Moiety for Targeted Protein Degradation via CRL4DCAF11Recruitment DOI Creative Commons

Ying Wanga,

Tianzi Wei,

Man Zhao

et al.

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

Published: Feb. 15, 2024

Abstract Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl targeted degradation, we designed and synthesized a series hetero-bifunctional by conjugating different with BRD4 inhibitor JQ1. Through structure-activity relationship study, successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, found these molecules through ubiquitin-proteasome system, rather than autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, revealed recruit E3 ubiquitin ligase complex CRL4 DCAF11 substrate Furthermore, validated most potent molecule HL435 promising drug-like lead compound exert antitumor activity both in vitro vivo . Our research provides new employable PROTAC moieties providing possibilities drug discovery.

Language: Английский

Distinct Amino Acid-Based PROTACs Target Oncogenic Kinases for Degradation in Non-Small Cell Lung Cancer (NSCLC) DOI
Jianchao Zhang, Xiao Chen,

Congli Chen

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(16), P. 13666 - 13680

Published: Aug. 8, 2024

Proteolysis-targeting chimeras (PROTACs) selectively eliminate detrimental proteins by exploiting the ubiquitin-proteasome system (UPS), representing a promising therapeutic strategy against various diseases. Effective adaptations of degradation signal sequences and E3 ligases for PROTACs remain limited. Here, we employed three amino acids─Gly, Pro, Lys─as ligand to recruit corresponding ligases: CRL2

Language: Английский

Citations

2
Proteolysis Targeting Chimeras (PROTACs) in Breast Cancer Therapy DOI Creative Commons
Yerim Jin, Yeongju Lee

ChemMedChem, Journal Year: 2024, Volume and Issue: 19(23)

Published: Aug. 13, 2024

Abstract Breast cancer (BC) accounts for 30 % of cases among women patients globally, indicating the urgent need development selective therapies targeting BCs. Recently, proteolysis‐targeting chimera (PROTAC) has emerged as a promising strategy to target breast cancer. PROTAC is chimeric molecule consisting protein ligand, an E3 ligase and conjugating linkers, enabling it facilitate degradation desired proteins by recruiting in close proximity. Due catalytic behavior direct BC‐causing proteins, could achieve high drug efficacy with low doses, drawing great attention its potential therapeutics. This review provides currently developed PROTACs BCs depending on type BCs, limitations, future perspectives

Language: Английский

Citations

2
Dual therapeutic targeting of MYC and JUNB transcriptional programs for enhanced anti-myeloma activity DOI Creative Commons
Judith Lind, Osman Aksoy,

Michaela Prchal‐Murphy

et al.

Blood Cancer Journal, Journal Year: 2024, Volume and Issue: 14(1)

Published: Aug. 19, 2024

Deregulation of transcription factors (TFs) leading to uncontrolled proliferation tumor cells within the microenvironment represents a hallmark cancer. However, biological and clinical impact transcriptional interference, particularly in multiple myeloma (MM) cells, remains poorly understood. The present study shows for first time that MYC JUNB, two crucial TFs implicated MM pathogenesis, orchestrate distinct programs. Specifically, our data revealed expression levels MYC, their respective downstream targets do not correlate global chromatin-binding patterns are significantly overlapping. Mechanistically, was affected by JUNB knockdown, conversely, activity were knockdown. Moreover, suppression via targeting master regulator BRD4 either siRNA-mediated knockdown or treatment with novel proteolysis chimera (PROTAC) MZ-1 overcame bone marrow (BM) stroma cell/IL-6-induced MYC- but MEK-dependent JUNB-upregulation activity. Consequently, non-overlapping JUNB-transcriptoms combination genetic pharmacological JUNB-targeting approaches synergistically enhanced cell death, both 2D dynamic 3D models BM milieu as well murine xenografts. In summary, emphasize opportunity employ dual-targeting strategies another exciting approach further improve patient outcomes.

Language: Английский

Citations

2
Recent advances in dual PROTACs degrader strategies for disease treatment DOI
Jianyu Liu, Yanzhuo Liu,

Jiao Tang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 279, P. 116901 - 116901

Published: Sept. 27, 2024

Language: Английский

Citations

2
Discovery of Alkenyl Oxindole as a Novel PROTAC Moiety for Targeted Protein Degradation via CRL4DCAF11Recruitment DOI Creative Commons

Ying Wanga,

Tianzi Wei,

Man Zhao

et al.

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

Published: Feb. 15, 2024

Abstract Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl targeted degradation, we designed and synthesized a series hetero-bifunctional by conjugating different with BRD4 inhibitor JQ1. Through structure-activity relationship study, successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, found these molecules through ubiquitin-proteasome system, rather than autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, revealed recruit E3 ubiquitin ligase complex CRL4 DCAF11 substrate Furthermore, validated most potent molecule HL435 promising drug-like lead compound exert antitumor activity both in vitro vivo . Our research provides new employable PROTAC moieties providing possibilities drug discovery.

Language: Английский

Citations

1