Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(7), P. 5275 - 5304

Published: March 13, 2024

CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer other types human cancers. Herein, we report discovery characterization CBPD-268 as an exceptionally potent, effective, orally efficacious PROTAC degrader proteins. induces degradation in three androgen receptor-positive cell lines, with DC50 ≤ 0.03 nM Dmax > 95%, leading to potent growth inhibition. It has excellent oral bioavailability mice rats. Oral administration at 0.3–3 mg/kg resulted profound persistent depletion tumor tissues achieved strong antitumor activity VCaP 22Rv1 xenograft models mice, including regression model. was well tolerated rats displayed a therapeutic index >10. Taking these results together, is highly potential new therapy.

Language: Английский

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Sulfatase-Induced In Situ Formulation of Antineoplastic Supra-PROTACs

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(15), P. 10753 - 10766

Published: April 5, 2024

Proteolysis targeting chimera (PROTAC) technology is an innovative strategy for cancer therapy, which, however, suffers from poor delivery and limited capability protein of interest (POI) degradation. Here, we report a the in situ formulation antineoplastic Supra-PROTACs via intracellular sulfatase-responsive assembly peptides. Coassembling sulfated peptide with two ligands binding to ubiquitin VHL Bcl-xL leads formation pro-Supra-PROTAC, which ratio rationally optimized based on their affinity. The resulting pro-Supra-PROTAC precisely undergoes enzyme-responsive into nanofibrous cells overexpressing sulfatase. Mechanistic studies reveal that pro-Supra-PROTACs selectively cause apparent cytotoxicity through degradation activation caspase-dependent apoptosis, during ligand improves bioactivity POI cell death. In vivo show enhanced tumor accumulation retention pro-Supra-PROTACs, as well inhibiting growth excellent biosafety when coadministrating chemodrugs. Our findings provide new approach enzyme-regulated peptides living development PROTACs high delivering efficiency.

Language: Английский

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Journey of PROTAC: From Bench to Clinical Trial and Beyond

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

Published: Jan. 10, 2025

Proteolysis-targeting chimeras (PROTACs) represent a transformative advancement in drug discovery, offering method to degrade specific intracellular proteins. Unlike traditional inhibitors, PROTACs are bifunctional molecules that target proteins for elimination, enabling the potential treatment of previously "undruggable" This concept, pioneered by Crews and his team, introduced use small link protein an E3 ubiquitin ligase, inducing ubiquitination subsequent degradation protein. By promoting rather than merely inhibiting function, present novel therapeutic strategy with enhanced specificity effectiveness, especially areas such as cancer neurodegenerative diseases. Since their initial field PROTAC research has rapidly expanded numerous now designed wide range disease-relevant The substantial research, investment, collaboration across academia pharmaceutical industry reflect growing interest PROTACs. Review discusses journey from discovery clinical trials, highlighting advancements challenges. Additionally, recent developments fluorescent photogenic PROTACs, used real-time tracking degradation, presented, showcasing evolving targeted therapy.

Language: Английский

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Functional Characterization of Pathway Inhibitors for the Ubiquitin-Proteasome System (UPS) as Tool Compounds for CRBN and VHL-Mediated Targeted Protein Degradation

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: 20(1), P. 94 - 104

Published: Jan. 3, 2025

Small molecule degraders such as PROteolysis TArgeting Chimeras (PROTACs) and molecular glues are new modalities for drug development important tools target validation. When appropriately optimized, both lead to proteasomal degradation of the protein interest (POI). Due complexity induced multistep process, controls degrader evaluation critical commonly used in literature. However, comparative studies evaluations cellular potencies these control compounds have not been published so far. Here, we investigated a diverse set ubiquitin pathway inhibitors evaluated their potency utility within CRBN VHL-mediated pathway. We HiBiT system measure level rescue after treatment with compounds. In addition, cell health was assessed using multiplexed high-content assay. These assays allowed us determine nontoxic effective concentrations experiments perform absence toxicity.

Language: Английский

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BRD4-targeted photodegradation nanoplatform for light activatable melanoma therapy

Biomaterials, Journal Year: 2025, Volume and Issue: 317, P. 123101 - 123101

Published: Jan. 10, 2025

Language: Английский

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