Cited by Discovery of a Potent, selective and orally bioavailable CDK9 degrader for targeting transcription regulation in Triple-Negative breast cancer

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

Zhixiang Chen, Biao Hu, Rohan Kalyan Rej

et al.

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

Citations

Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs DOI

Rohan Kalyan Rej, Srinivasa Rao Allu, Joyeeta Roy

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(4), P. 494 - 494

Published: April 12, 2024

Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality that show promise to open a target space not accessible conventional small molecules via degradation-based mechanism. PROTAC degraders, due their bifunctional nature, which is categorized as ‘beyond the Rule of Five’, have gained attention distinctive approach for oral administration in clinical settings. However, development PROTACs with adequate bioavailability remains significant hurdle, largely large size and less than ideal physical chemical properties. This review encapsulates latest advancements orally delivered entered evaluation well developments highlighted recent scholarly articles. The insights methodologies elaborated upon this could be instrumental supporting discovery refinement novel degraders aimed at treatment various human cancers.

Language: Английский

Citations

Journey of Von Hippel-Lindau (VHL) E3 ligase in PROTACs design: From VHL ligands to VHL-based degraders DOI

Nisha Setia,

Haider Thaer Abdulhameed Almuqdadi, Mohammad Abid

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 265, P. 116041 - 116041

Published: Dec. 13, 2023

Language: Английский

Citations

Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα) DOI

Rohan Kalyan Rej, Biao Hu, Zhixiang Chen

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 25, 2024

Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment ER-positive (ER+) breast cancers, but new strategies are urgently needed to overcome clinical resistance. In present study, we describe discovery and extensive evaluation ERD-12310A as exceptionally potent orally efficacious PROTAC degrader ERα. achieved a DC

Language: Английский

Citations

Structure–Activity Relationship (SAR) Studies of Novel Monovalent AR/AR-V7 Dual Degraders with Potent Efficacy against Advanced Prostate Cancer DOI

Maoxu Xiao,

Si Ha,

Jiacheng Zhu

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(7), P. 5567 - 5590

Published: March 21, 2024

Androgen receptor (AR) has been extensively established as a potential therapeutic target for nearly all stages of prostate cancer (PCa). However, acquired resistance to AR-targeted drugs inevitably develops and severely limits their clinical efficacy. Particularly, there currently exists no efficient treatment patients expressing the constitutively active AR splice variants, such AR-V7. Herein, we report structure–activity relationship studies 55 N-heterocycle-substituted hydantoins, which identified structural motifs required AR/AR-V7 degradation. Among them, most potent compound 27c exhibited selective degradation over other hormone receptors excellent antiproliferative activities in LNCaP 22RV1 cells. RNA sequence analysis confirmed that effectively suppressed transcriptional activity signaling pathway. Importantly, demonstrated antitumor efficacy an enzalutamide-resistant xenograft model. These results highlight promising dual degrader overcoming drug advanced PCa variants.

Language: Английский

Citations

Design, Synthesis, and Biological Evaluation of Novel BTK-targeting Proteolysis Targeting Chimeras (PROTACs) with Enhanced Pharmacokinetic Properties DOI

Ying‐Hung Lin, Jing Liu, Xiaohe Tian

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 289, P. 117420 - 117420

Published: Feb. 22, 2025

Language: Английский

Citations

Predicting PROTAC-targeted Degradation and Designing Androgen Receptor Degraders with AiPROTAC DOI

Li Zhang, Renhong Sun, Xia Li

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 2, 2025

ABSTRACT Proteolysis-targeting chimeras (PROTACs), a pioneering class of heterobifunctional ligands, have emerged as transformative tools in combating cancer and immune-related diseases due to their ability target previously undruggable proteins overcome drug resistance. Accurate assessment the degradation potential PROTACs is essential for advancing therapeutic applications. However, development robust predictive models hindered by scarcity large-scale datasets domain-specific tools, well underutilization existing unlabeled data. To address these challenges, we developed an innovative method called AiPROTAC predict capacity PROTACs. In particular, integrates graph augmentation, message-passing enhanced encoders cross-attention mechanisms within contrastive learning framework. Moreover, leverages curated specialized dataset combined with PROTAC-DB enhance prediction accuracy. Experimental results across two six evaluation metrics demonstrate that consistently outperforms state-of-the-art models. Further case studies underline its superior sensitivity reliability. Notably, facilitated design novel androgen receptor (AR) degrader, PROTAC GT19, which achieved vitro compared Bavdegalutamide (ARV-110). This advancement highlights our AiPROTAC’s accelerate PROTAC-based optimization.

Language: Английский

Citations

PSMA-Guided PROTAC Degraders for Tumor-Specific Protein Degradation in Prostate Cancer DOI

Xiaolei Meng,

Xiaolin Hu, Shan Gao

et al.

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

Published: May 1, 2025

PROTACs that degrade target proteins to treat diseases represent a highly promising strategy in drug design. However, the degradation of nondisease tissues may lead systemic toxicity. Herein, capitalizing on characteristic overexpression PSMA prostate cancer, we devised PSMA-guided PROTACs-specific targeting cancer. By conjugation AR degraders and BET separately with ligands via cleavable linkers, two classes were obtained. In vitro experiments demonstrated selectively degraded PSMA-overexpressing cancer cells without affecting other cells. vivo studies revealed compared conventional PROTACs, enhanced exposure prolonged half-life consequently achieved stronger more sustained therapeutic effects. This work provides novel avenue for disease tissue-specific PROTAC research, holding significant implications targeted therapy

Language: Английский

Citations

Selective steroid receptor modulators, degraders and PROTACs: Therapeutic strategies in management of endocrine-related cancers DOI

Anjali Tripathi,

Ayushi Chhabra,

Sheeba Rizvi

et al.

Molecular and Cellular Endocrinology, Journal Year: 2025, Volume and Issue: unknown, P. 112569 - 112569

Published: May 1, 2025

Language: Английский

Citations

Click-constructed modular signal aptamer chimeras enable receptor-independent degradation of membrane proteins DOI

Wanlin Xie,

Weidi Sun,

Qin Li

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(21)

Published: May 19, 2025

Cell-membrane proteins are critical mediators of signal transduction, playing essential roles in disease occurrence and progression. The emerging LYTACs (Lysosome-targeting chimeras) technology combines drug-targeting strategies with lysosomal degradation, providing a novel approach to drug development offering new possibilities for therapy. However, the clinical applicability current LYTAC degraders is limited by variable expression lysosome-targeting receptors (LTRs) tissues. To overcome this limitation, we herein hijacked YXXØ sorting that derived from lysosome-associated membrane protein 2a (LAMP-2a) develop aptamer platform (SApt), which exhibits high specificity targeting inducing efficient degradation. SApts were synthesized conjugating peptide aptamer’s terminus through click reaction. Our study demonstrated efficiently degrade disease-associated proteins, such as PTK7, Met, NCL, based on inherent signals rather than specific LTR. potent antitumor efficacy was further confirmed xenograft tumor model, where vivo degradation PTK7 observed. Collectively, our work provides insights into simple universal potential translational value treatment.

Language: Английский

Citations