Design and Discovery of Preclinical Candidate LYG-409 as a Highly Potent and Selective GSPT1 Molecular Glue Degraders

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

Published: Jan. 24, 2025

Molecular glue degraders induce "undruggable" protein degradation by a proximity-induced effect. Inspired the clinical success of immunomodulatory drugs, we aimed to design novel molecular targeting GSPT1. Here, report series GSPT1 degraders. LYG-409, 2H-chromene derivative, was identified as potent, selective, and orally bioavailable degrader with excellent antitumor activity in vivo (anti-Acute Myeloid Leukemia MV4–11 xenograft model: TGI = 94.34% at 30 mg/kg; prostate cancer 22Rv1 104.49% 60 mg/kg) vitro (KG-1 cells: IC50 9.50 ± 0.71 nM, DC50 7.87 nM) mediated In conclusion, LYG-409 exhibits potent activity, demonstrating promising therapeutic efficacy favorable safety profile. However, its potential drug resistance profile needs be thoroughly evaluated comparison existing treatments. We hope can provide valuable direction for development

Language: Английский

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Discovery of the First Potent ROR1 Degrader for the Treatment of Non-Small Cell Lung Cancer

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

Published: Jan. 1, 2025

Language: Английский

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Genetically-encoded targeted protein degradation technology to remove endogenous condensation-prone proteins and improve crop performance

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 29, 2025

Effective modulation of gene expression in plants is achievable through tools like CRISPR and RNA interference, yet methods for directly modifying endogenous proteins remain lacking. Here, we identify the E3 ubiquitin ligase E3TCD1 develope a Targeted Condensation-prone-protein Degradation (TCD) strategy. The X-E3TCD1 fusion protein acts as genetically engineered degrader, selectively targeting prone to condensation. For example, transgenic with Teosinte branched 1 (TB1) degrades native TB1 protein, resulting increased tiller numbers rice. Additionally, conditional degradation negative defense regulator Early Flowering 3 via pathogen-responsive ProTBF1-uORFsTBF1 cassette enhances rice blast resistance without affecting flowering time absence pathogen. Unlike prevailing targeted strategies, TCD system does not rely on small molecules, antibodies, or genetic knock-in tags, demonstrating its promise transgene-based approach optimizing crop performance.

Language: Английский

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Identification of actionable targeted protein degradation effector sites through Site-specific Ligand Incorporation-induced Proximity (SLIP)

Published: Feb. 4, 2025

ABSTRACT Targeted protein degradation (TPD) is a rapidly emerging and potentially transformative therapeutic modality. However, the large majority of >600 known ubiquitin ligases have yet to be exploited as TPD effectors by proteolysis-targeting chimeras (PROTACs) or molecular glue degraders (MGDs). We report here chemical–genetic platform, Site-specific Ligand Incorporation-induced Proximity (SLIP), identify actionable (“PROTACable”) sites on any potential effector in intact cells. SLIP uses genetic code expansion (GCE) encode copper-free “click” ligation at specific site cells, enabling situ formation covalent PROTAC-effector conjugate against target interest (POI). Modification drives targeted protein, establishing these for TPD. Using SLIP, we systematically screened dozens across E3 E2 enzymes from diverse classes, identifying multiple novel PROTACable which are competent adds powerful approach proximity-induced pharmacology (PIP) toolbox, future ligand discovery fully enable TPD, other PIP modalities.

Language: Английский

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Proteolysis-Targeting Chimera-Doxorubicin Conjugate Nanoassemblies for Dual Treatment of EGFR-TKI Sensitive and Resistant Non-Small Cell Lung Cancer

Acta Biomaterialia, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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