Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs DOI Creative Commons
Christian Steinebach, Aleša Bricelj, Arunima Murgai

и другие.

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(21), С. 14513 - 14543

Опубликована: Окт. 30, 2023

Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce degradation of IMiD neosubstrates inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, off-target neosubstrate modulation features to develop novel nonphthalimide binders. These efforts led discovery conformationally locked benzamide-type derivatives that replicate interactions natural degron, exhibit enhanced chemical display a favorable selectivity profile terms recruitment. The utility potent was demonstrated by their transformation into degraders BRD4 HDAC6 outperform previously described reference PROTACs. Together with significantly decreased neomorphic ligase activity on IKZF1/3 SALL4, provide opportunities for design highly selective chemically inert proximity-inducing compounds.

Язык: Английский

PROTACs: A novel strategy for cancer drug discovery and development DOI Creative Commons
Xin Han, Yi Sun

MedComm, Год журнала: 2023, Номер 4(3)

Опубликована: Май 29, 2023

Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: small molecule that binds to target protein, an E3 ligase ligand (consisting and its recruiter), chemical linker hooks first two components together. In the past 20 years, we have witnessed advancement multiple degraders into clinical trials anticancer therapies. However, one major challenges is only very limited number recruiters are currently available as targeted protein degradation (TPD), although human genome encodes more than 600 ligases. Thus, there urgent need identify additional effective TPD applications. this review, summarized existing RING-type ubiquitin their act ligands application discovery. We believe review could serve reference future development efficient cancer discovery development.

Язык: Английский

Процитировано

26
CircRNF10 triggers a positive feedback loop to facilitate progression of glioblastoma via redeploying the ferroptosis defense in GSCs DOI Creative Commons
Chengbin Wang, Minjie Zhang, Yingliang Liu

и другие.

Journal of Experimental & Clinical Cancer Research, Год журнала: 2023, Номер 42(1)

Опубликована: Сен. 19, 2023

Glioma exhibit heterogeneous susceptibility for targeted ferroptosis. How circRNAs alterations in glioma promote iron metabolism and ferroptosis defense remains unclarified.The highly enriched glioblastoma (GBM) were obtained through analysis of sequencing datasets. Quantitative real-time PCR (qRT-PCR) was used to determine the expression circRNF10 normal brain tissue. Both gain-of-function loss-of-function studies assess effects on using vitro vivo assays. The hypothesis that ZBTB48 promotes established bioinformatics functional RNA pull-down immunoprecipitation (RIP) assays performed examine interaction between target proteins including ZBTB48, MKRN3 IGF2BP3. posttranslational modification mechanism verified coimmunoprecipitation (co-IP) ubiquitination transcription activation HSPB1 IGF2BP3 by confirmed luciferase reporter gene chromatin (ChIP) stabilizing effect explored actinomycin D assay. Finally, a series experiments explore influences progression.A novel circular RNA, hsa_circ_0028912 (named circRNF10), which is significantly upregulated tissues correlated with patients' poor prognosis. Through integrated circRNA-proteins datasets results, we reveal as transcriptional factor binding circRNF10, notably promoting upregulation remodel facilitates launch circRNF10/ZBTB48/IGF2BP3 positive feedback loop GSCs. Additionally, can competitively bind block E3 ubiquitin ligase activity enhance expression. Consequently, circRNF10-overexpressed stem cells (GSCs) display lower Fe2+ accumulation, selectively priming tumors evading.Our research presents abnormal causing molecular metabolic change glioma, leverage discover therapeutically exploitable vulnerability

Язык: Английский

Процитировано

25
Discovery of Effective Dual PROTAC Degraders for Neurodegenerative Disease-Associated Aggregates DOI
Wentao Zhu,

Wenqian Zhang,

Jian Chen

и другие.

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(5), С. 3448 - 3466

Опубликована: Фев. 15, 2024

The aggregation of specific proteins is a histopathological hallmark in various neurodegenerative diseases (NDs), among which Alpha-synuclein (α-Syn) and tau have received increased attention. targeted protein degradation (TPD) strategy has been studied the treatment NDs, but multitarget bifunctional molecules ignored. Herein, series effective dual PROTAC degraders were developed, could degrade α-Syn aggregates total simultaneously. effects evaluated vitro, results showed that T3 significantly knockdown efficiency with DC50 1.57 ± 0.55 4.09 0.90 μM, respectively. Further mechanistic exploration effect was mediated by ubiquitin–proteasome system (UPS). Additionally, therapeutic efficacy confirmed an MPTP-induced PD mouse model. Our suggest these PROTACs may provide potential for NDs.

Язык: Английский

Процитировано

15
Targeting focal adhesion kinase (FAK) for cancer therapy: FAK inhibitors, FAK-based dual-target inhibitors and PROTAC degraders DOI
Ming Yang, Hua Xiang, Guoshun Luo

и другие.

Biochemical Pharmacology, Год журнала: 2024, Номер 224, С. 116246 - 116246

Опубликована: Апрель 27, 2024

Язык: Английский

Процитировано

15
A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy DOI Creative Commons
Jing Gao, Xingyu Jiang,

Shumin Lei

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 4, 2024

The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. These disadvantages are further compounded heterogeneity, especially the presence cancer stem-like cells, which drive growth relapse. Herein, we design a region-confined PROTAC nanoplatform that integrates both reactive oxygen species (ROS)-activatable hypoxia-responsive prodrugs for precise manipulation bromodomain extraterminal protein 4 expression eradication. nanoparticles selectively accumulate within penetrate deep into tumors via response to matrix metalloproteinase-2. Photoactivity then reactivated in acidic intracellular milieu discharged due ROS generated photodynamic therapy specifically normoxic microenvironment. Moreover, latent prodrug restored hypoxic cells overexpressing nitroreductase. Here, show ability effectively degrade BRD4 environments, markedly hindering progression breast head-neck models.

Язык: Английский

Процитировано

15
What influences the activity of Degrader−Antibody conjugates (DACs) DOI
Yaolin Guo,

Xiaoxue Li,

Yang Xie

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 268, С. 116216 - 116216

Опубликована: Фев. 3, 2024

Язык: Английский

Процитировано

13
Accelerating PROTACs Discovery Through a Direct‐to‐Biology Platform Enabled by Modular Photoclick Chemistry DOI Creative Commons

Ke‐Nian Yan,

Yong‐Qiang Nie,

Jiayu Wang

и другие.

Advanced Science, Год журнала: 2024, Номер 11(26)

Опубликована: Апрель 30, 2024

Abstract Proteolysis targeting chimeras (PROTACs) have emerged as a promising strategy for drug discovery and exploring protein functions, offering revolutionary therapeutic modality. Currently, the predominant approach to PROTACs mainly relies on an empirical design–synthesis–evaluation process involving numerous cycles of labor‐intensive synthesis‐purification bioassay data collection. Therefore, development innovative methods expedite PROTAC synthesis exploration chemical space remains highly desired. Here, direct‐to‐biology is reported streamline libraries plates, enabling seamless transfer reaction products cell‐based bioassays without need additional purification. By integrating amide coupling light‐induced primary amines o‐nitrobenzyl alcohols cyclization (PANAC) photoclick chemistry into plate‐based synthetic process, this produces with high efficiency structural diversity. Moreover, by employing platform screening, we smoothly found potent effectively inhibit triple‐negative breast cancer (TNBC) cell growth induce rapid, selective targeted degradation cyclin‐dependent kinase 9 (CDK9). The study introduces versatile assembling followed direct biological evaluation. This provides opportunity high‐throughput libraries, thereby enhancing accelerating PROTACs.

Язык: Английский

Процитировано

11
Innovative, combinatorial and high-throughput approaches to degrader synthesis DOI
Rebecca Stevens, James D. F. Thompson, Julie C. L. Fournier

и другие.

Chemical Society Reviews, Год журнала: 2024, Номер 53(10), С. 4838 - 4861

Опубликована: Янв. 1, 2024

In this review we highlight how the synthesis of degraders has evolved in recent years, particular application high-throughput chemistry and screening approaches such as D2B DEL technologies to expedite discovery timelines.

Язык: Английский

Процитировано

10
Targeting androgen receptor degradation with PROTACs from bench to bedside DOI Open Access

Xiaojuan Jia,

Xin Han

Biomedicine & Pharmacotherapy, Год журнала: 2022, Номер 158, С. 114112 - 114112

Опубликована: Дек. 9, 2022

Inhibition of androgen receptor (AR) has been extensively investigated to treat prostate cancer. Resistance mechanisms such as increased levels production, AR gene, enhancer expression and point mutations always reduce the clinical efficacy. Design discovery small-molecule PROTAC degraders have pursued a new therapeutic strategy overcome common resistance developed during cancer treatment. In last two decades, potent efficacious gotten rapid development several compounds advanced into preclinical phase I/II trials for treatment human cancers. Especially, first enter clinic, ARV-110, shown good effects in patients with mCRPC. This fully demonstrates high value diseases. Here, we summarized recent advances these potential clinical-stage degraders.

Язык: Английский

Процитировано

37
Targeting the deubiquitinase USP7 for degradation with PROTACs DOI
Arunima Murgai, Izidor Sosič, Martina Gobec

и другие.

Chemical Communications, Год журнала: 2022, Номер 58(63), С. 8858 - 8861

Опубликована: Янв. 1, 2022

A novel class of USP7 PROTACs were designed and synthesized. CST967, a CRBN-based degrader, showed potent selective depletion leading to apoptosis in multiple cancer lines.

Язык: Английский

Процитировано

34