Synthesis, SAR, and application of JQ1 analogs as PROTACs for cancer therapy

Bioorganic & Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 112, P. 117875 - 117875

Published: Aug. 16, 2024

Language: Английский

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Shh–Gli2–Runx2 inhibits vascular calcification

Nephrology Dialysis Transplantation, Journal Year: 2023, Volume and Issue: 39(2), P. 305 - 316

Published: July 14, 2023

ABSTRACT Background In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and associated a higher risk of all-cause mortality. Shh, one ligand for Hedgehog (Hh) signaling, participates in osteogenesis several cardiovascular diseases. However, it remains unclear whether Shh implicated the development VC. Methods Inorganic phosphorus 2.6 mM was used to induce smooth muscle cells (VSMCs) calcification. Mice were fed adenine diet supplement 1.2% Results decreased VSMCs exposed inorganic phosphorus, calcified arteries mice an diet, as well radial from CKD presenting Overexpression inhibited ostosteoblastic differentiation calcification, whereas its silencing accelerated these processes. Likewise, treated smoothened agonist (SAG; Hh signaling agonist) showed alleviated VC, cyclopamine (CPN; antagonist) exhibited severe Additionally, overexpression Gli2 significantly reversed pro-calcification effect on VSMCs, suggesting that VC via Gli2. Mechanistically, interacted Runx2 promoted ubiquitin proteasomal degradation, therefore protecting against Of interest, pro-degradation independent Smurf1 Cullin4B. Conclusions Our study provided deeper insight pathogenesis might be novel potential target treatment.

Language: Английский

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Construction and characterization of Fe ₃ O ₄ @BAAH-CuCl nanomagnetic catalyst: catalysis research in synthesis of 2-aryl quinazolines from prepared benzylamines

Journal of Coordination Chemistry, Journal Year: 2024, Volume and Issue: 77(5-6), P. 448 - 465

Published: March 3, 2024

We have constructed Fe3O4@BAAH-CuCl nanomagnetic catalyst in ChCl-Urea (choline chloride deep eutectic as solvent) a highly efficient catalytic system for the preparation of 2-aryl quinazoline derivatives through one-pot, three-component reactions 2-bromobenzaldehyde with primary amines and sodium azide under molecular oxygen. FT-IR, VSM, SEM, TEM, TGA, XRD, EDX, ICP-OES elemental mapping analyses confirmed fabrication nanomaterial. In this project, we first prepared various benzylamines from reduction aryl nitriles, then used benzylamine products substrates synthesis presence Fe3O4@BAAH-CuCl/ChCl-Urea an system. Although synthesized (primary quinazolines) were known, their physical state was reported samples literature structure all by 1HNMR 1CNMR.

Language: Английский

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PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

MedComm, Journal Year: 2024, Volume and Issue: 5(6)

Published: June 1, 2024

Abstract Leukemia is a heterogeneous group of life‐threatening malignant disorders the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, long‐term sequelae occur in significant proportion patients severely compromise treatment efficacy. The development novel approaches to improve outcomes therefore an unmet need. Recently, drug discovery strategies, including protein degradation, have shown potential advance field personalized medicine for patients. Specifically, PROteolysis‐TArgeting Chimeras (PROTACs) revolutionary compounds that allow selective degradation by ubiquitin–proteasome Developed against wide range cancer targets, they show promising overcoming many drawbacks associated with conventional therapies. Following exponential growth antileukemic PROTACs, this article reviews PROTAC‐mediated leukemia‐associated targets. Chemical structures, vitro vivo activities, pharmacokinetics, pharmacodynamics, clinical trials PROTACs critically discussed. Furthermore, advantages, challenges, future perspectives covered, order understand these may as drugs treatment.

Language: Английский

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Construction of Pd Complex Immobilized on Magnetic Nanoparticles as an Efficient Nanocatalyst for Preparation of Diaryl Ketones

Journal of Inorganic and Organometallic Polymers and Materials, Journal Year: 2024, Volume and Issue: unknown

Published: July 17, 2024

Language: Английский

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Treating ICB-Resistant Cancer by Inhibiting PD-L1 via DHHC3 Degradation Induced by Cell Penetrating Peptide-Induced Chimera Conjugates

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 2, 2024

The current selection of ligands for both proteins interest (POI) and E3 ubiquitin ligase significantly restricts the scope targeted protein degradation (TPD) technologies. This study introduces cell-penetrating peptide-induced chimera conjugates (cp-PCCs) targeting DHHC3 enzyme involved in PD-L1 palmitoylation. approach disrupts PD-L1's immunosuppressive function, enhancing anti-tumor immunity. We developed cp-PCCs to degrade DHHC3, directly linking DHHC3-mediated palmitoylation stability on tumor cells. Our research utilized vitro assays vivo experiments immune checkpoint blockade-resistant mouse models. focused a CRBN-based cp-PCC named PCC16, which demonstrated DC50 102 nmol reduced levels. In resistant models, PCC16 not only robustly downregulated but also exhibited substantial activity without significant toxicity. outperformed traditional inhibitors, showcasing potential technology bypass PROTAC limitations. findings suggest that offer promising method through inhibition support their continued exploration as versatile tool cancer immunotherapy, especially tumors standard treatments.

Language: Английский

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Protacs in cancer therapy: mechanisms, design, clinical trials, and future directions

Drug Delivery and Translational Research, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 29, 2024

Language: Английский

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Nanotechnology‐Enabled Targeted Protein Degradation for Cancer Therapeutics

Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology, Journal Year: 2024, Volume and Issue: 16(6)

Published: Nov. 1, 2024

ABSTRACT Targeted protein degradation (TPD) represents an innovative therapeutic strategy that has garnered considerable attention from both academic and industrial sectors due to its promising developmental prospects. Approximately 85% of human proteins are implicated in disease pathogenesis, the FDA approved around 400 drugs targeting these disease‐related proteins, predominantly enzymes, transcription factors, non‐enzymatic proteins. However, existing modalities fail address certain “high‐value” targets, such as c‐Myc Ras. The emergence proteolysis‐targeting chimeras (PROTAC) technology introduced TPD into a new realm. capability target non‐druggable sites expanded horizon protein‐based drugs, although challenges related bioavailability, safety, adverse side effects have constrained their clinical progression. Nano‐delivery systems emerging modalities, molecular glues, lysosome‐targeted (LYTACs), autophagy system compounds (ATTEC), antibody PROTAC (AbTACs), mitigated some limitations. This paper reviews latest advancements TPD, highlighting applications benefits cancer therapy, concludes with forward‐looking perspective on future development this field.

Language: Английский

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PROTAC^® technology and potential for its application in infection control

Fine Chemical Technologies, Journal Year: 2024, Volume and Issue: 19(3), P. 214 - 231

Published: July 6, 2024

Objectives. To describe the pharmaceutical technology of controlled degradation protein molecules (PROTAC ® , Proteolysis Targeting Chimera), approaches to design PROTAC molecule, methods ligand and linker selection synthesis, as well application this in dealing with a variety diseases possible limitations its use. Results. The review covers 77 sources, mostly from 2020–2023. outlines principle technology: construction chimeric molecule consisting three fragments. One fragment specifically binds biotarget, another recruits proteolytic system host cell, third them together. main areas current development are described herein, opportunities fight against different types infectious diseases. Conclusion. potential use combat cancer neurodegenerative, autoimmune, is shown.

Language: Английский

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Discovery of a Natural Ent-Kaurene Diterpenoid Oridonin as an E3 Ligase Recruiter for PROTACs

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

Published: Dec. 30, 2024

PROTACs have emerged as a therapeutic modality for the targeted degradation of proteins interest (POIs). Central to PROTAC technology are E3 ligase recruiters, yet only few them been identified due lack ligandable pockets in ligases, especially among single-subunit ligases. We propose that binders partner ligases could be repurposed new recruiters. MDM2 is overexpressed tumors. Nucleolin (NCL) an protein displays similar tumor-specific overexpression pattern and nuclear-cytoplasmic shuttling role MDM2. Furthermore, NCL selectively translocated on tumor cell surface, where it acts internalization receptor its binders. reveal NCL-binding Oridonin (Ori), natural ent-kaurene diterpenoid, capable recruiting by employing molecular bridge. design Ori-based modulating oncogenic POIs, including BRD4 EGFR. These direct assembly MDM2-NCL-PROTAC-POI complexes induce proteasomal POIs shrinkage. In addition engaged PROTACs, MDM2, along with homologue MDMX, plays nonredundant function inhibiting p53 activity. Dual inhibition MDM2/X proposed promising antitumor strategy. demonstrate Ori also recruits MDMX NCL-dependent manner. homo-PROTACs dual attenuate progression. Our findings prove feasibility repurposing recruiters highlight potential recruiter.

Language: Английский

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