Characteristic roadmap of linker governs the rational design of PROTACs

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(10), P. 4266 - 4295

Published: April 11, 2024

Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected linker. The linker plays pivotal role determining PROTAC's biodegradative efficacy. Advanced and rationally designed linkers are under development. Nonetheless, correlation between characteristics efficacy remains under-investigated. Consequently, this study will present multidisciplinary analysis of their impact on efficacy, thereby guiding rational design linkers. We primarily discuss structural types linkers, optimization strategies used design. Furthermore, we how factors like length, group type, flexibility, linkage site affect biodegradation efficiency PROTACs. believe that work contribute towards advancement research area.

Language: Английский

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Structural and Physicochemical Features of Oral PROTACs

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(15), P. 13106 - 13116

Published: July 30, 2024

Achieving oral bioavailability with Proteolysis Targeting Chimeras (PROTACs) is a key challenge. Here, we report the in vivo pharmacokinetic properties mouse, rat, and dog of four clinical PROTACs compare an internally derived data set. We use NMR to determine 3D molecular conformations structural preorganization free solution, introduce new experimental descriptors, solvent-exposed H-bond donors (eHBD), acceptors (eHBA). derive upper limit eHBD ≤ 2 for apolar environments show greater tolerance other (eHBA, polarity, lipophilicity, weight) than Rule-of-5 compliant drugs. Within set structurally related PROTACs, that examples > have much lower those 2. summarize our findings as "Rule-of-oral-PROTACs" order assist medicinal chemists achieve this challenging space.

Language: Английский

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Current advances and development strategies of orally bioavailable PROTACs

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 261, P. 115793 - 115793

Published: Sept. 7, 2023

Language: Английский

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Discovery of ARD-1676 as a Highly Potent and Orally Efficacious AR PROTAC Degrader with a Broad Activity against AR Mutants for the Treatment of AR + Human Prostate Cancer

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(18), P. 13280 - 13303

Published: Sept. 8, 2023

We report herein the discovery and extensive characterization of ARD-1676, a highly potent orally efficacious PROTAC degrader androgen receptor (AR). ARD-1676 was designed using new class AR ligands novel cereblon ligand. It has DC50 values 0.1 1.1 nM in AR+ VCaP LNCaP cell lines, respectively, IC50 11.5 2.8 respectively. effectively induces degradation broad panel clinically relevant mutants. an oral bioavailability 67, 44, 31, 99% mice, rats, dogs, monkeys, Oral administration reduces level protein tumor tissue mice inhibits growth mouse xenograft model without any sign toxicity. is promising development candidate for treatment human prostate cancer.

Language: Английский

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Insight into Recent Advances in Degrading Androgen Receptor for Castration-Resistant Prostate Cancer

Cancers, Journal Year: 2024, Volume and Issue: 16(3), P. 663 - 663

Published: Feb. 4, 2024

Induced protein degradation has emerged as an innovative drug discovery approach, complementary to the classical method of suppressing function. The androgen receptor signaling pathway been identified primary driving force in development and progression lethal castration-resistant prostate cancer. Since degraders function differently from antagonists, they hold promise overcome resistance challenges faced by current therapeutics. Proteolysis-targeting chimeras (PROTACs), monomeric degraders, hydrophobic tagging, molecular glues, autophagic have demonstrated their capability downregulating intracellular concentrations. potential these treat cancer is substantiated advancement six PROTACs two into phase I or II clinical trials. Although chemical structures, vitro vivo data, mechanisms reviewed, it crucial stay updated on recent advances this field novel new strategies continue emerge. This review thus provides insight advancements paradigm, offering overview progress made since 2020.

Language: Английский

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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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Proteolysis Targeting Chimera Degraders of the METTL3–14 m⁶A-RNA Methyltransferase

JACS Au, Journal Year: 2024, Volume and Issue: 4(2), P. 713 - 729

Published: Feb. 12, 2024

Methylation of adenine N6 (m6A) is the most frequent RNA modification. On mRNA, it catalyzed by METTL3–14 heterodimer complex, which plays a key role in acute myeloid leukemia (AML) and other types blood cancers solid tumors. Here, we disclose first proteolysis targeting chimeras (PROTACs) for an epitranscriptomics protein. For designing PROTACs, made use crystal structure complex with potent selective small-molecule inhibitor (called UZH2). The optimization linker started from desfluoro precursor UZH2 whose synthesis more efficient than that UZH2. nine PROTAC molecules featured PEG- or alkyl-based linkers, but only latter showed cell penetration. With this information hand, synthesized 26 PROTACs based on alkyl linkers different lengths rigidity. formation ternary was validated FRET-based biochemical assay vitro ubiquitination assay. 14, 20, 22, 24, 30, featuring lengths, 50% higher degradation METTL3 and/or METTL14 measured Western blot MOLM-13 cells. They also substantial three AML lines prostate cancer line PC3.

Language: Английский

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Application and challenges of nitrogen heterocycles in PROTAC linker

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 273, P. 116520 - 116520

Published: May 21, 2024

Language: Английский

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Discovery of CBPD-409 as a Highly Potent, Selective, and Orally Efficacious CBP/p300 PROTAC Degrader for the Treatment of Advanced Prostate Cancer

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(7), P. 5351 - 5372

Published: March 26, 2024

CBP/p300 are critical transcriptional coactivators of the androgen receptor (AR) and promising cancer therapeutic targets. Herein, we report discovery highly potent, selective, orally bioavailable degraders using PROTAC technology with CBPD-409 being most compound. induces robust degradation DC50 0.2–0.4 nM displays strong antiproliferative effects IC50 1.2–2.0 in VCaP, LNCaP, 22Rv1 AR+ prostate cell lines. It has a favorable pharmacokinetic profile achieves 50% oral bioavailability mice. A single administration at 1 mg/kg >95% depletion proteins VCaP tumor tissue. exhibits growth inhibition is much more potent efficacious than two inhibitors CCS1477 GNE-049 AR antagonist Enzalutamide. degrader for further extensive evaluations treatment advanced other types human cancers.

Language: Английский

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Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(17), P. 12559 - 12585

Published: Aug. 30, 2023

Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite development several effective therapies targeting ERα signaling, clinical resistance remains major challenge. In this study, we report discovery new class potent and orally bioavailable degraders using PROTAC technology, with ERD-3111 being most promising compound. exhibits in vitro degradation activity against demonstrates high oral bioavailability mice, rats, dogs. Oral administration effectively reduces levels wild-type mutated proteins tumor tissues. achieves regression or complete growth inhibition parental MCF-7 xenograft model ER two clinically relevant ESR1 models mice. degrader further extensive evaluations ER+

Language: Английский

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