Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges

Wang, Chao; Zhang, Yujing; Zhang, Tingting; Shi, Lingyu; Geng, Zhongmin; Xing, Dongming

doi:10.1080/14756366.2022.2076675

Cited by 8 publications

(6 citation statements)

References 124 publications

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“…We can try to combine a wide range of specific inhibitors with different linkers or different E3 target segments to improve the selectivity of DAPKs by rational design. 207 The current challenges in drug development are finding the appropriate target, the design of the drug once the target has been identified, and preclinical pharmacokinetic studies. In recent years, artificial intelligence (AI) and machine learning (ML) have become integral tools for deriving significant insights and improving drug discovery strategies.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, targeted protein degradation technologies, such as proteolysis-targeting chimaera (PROTAC), have not been investigated with DAPKs as targets. We can try to combine a wide range of specific inhibitors with different linkers or different E3 target segments to improve the selectivity of DAPKs by rational design . The current challenges in drug development are finding the appropriate target, the design of the drug once the target has been identified, and preclinical pharmacokinetic studies.…”

Section: Discussionmentioning

confidence: 99%

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Targeting Death-Associated Protein Kinases for Treatment of Human Diseases: Recent Advances and Future Directions

et al. 2023

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The death-associated protein kinase (DAPK) family is a member of the calcium/calmodulin-regulated serine/threonine protein kinase family, and studies have shown that its role, as its name suggests, is mainly to regulate cell death. The DAPK family comprises five members, including DAPK1, DAPK2, DAPK3, DRAK1 and DRAK2, which show high homology in the common N-terminal kinase domain but differ in the extra-catalytic domain. Notably, previous research has suggested that the DAPK family plays an essential role in both the development and regulation of human diseases. However, only a few small-molecule inhibitors have been reported. In this Perspective, we mainly discuss the structure, biological function, and role of DAPKs in diseases and the currently discovered small-molecule inhibitors, providing valuable information for the development of the DAPK field.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting Death-Associated Protein Kinases for Treatment of Human Diseases: Recent Advances and Future Directions

et al. 2023

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“…[ 17 ] Despite progress made in rational PROTAC design via structural biology and computational simulations, [ 13b,14d,18 ] practical systematic linker SAR studies are still in great demand and have proven to be time and labor‐intensive. [ 19 ]…”

Section: Introductionmentioning

confidence: 99%

High‐Throughput Miniaturized Synthesis of PROTAC‐Like Molecules

Tian,

Seifermann,

Bauer

et al. 2024

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The development of miniaturized high‐throughput in situ screening platforms capable of handling the entire process of drug synthesis to final screening is essential for advancing drug discovery in the future. In this study, an approach based on combinatorial solid‐phase synthesis, enabling the efficient synthesis of libraries of proteolysis targeting chimeras (PROTACs) in an array format is presented. This on‐chip platform allows direct biological screening without the need for transfer steps. UV‐induced release of target molecules into individual droplets facilitates further on‐chip experimentation. Utilizing a mitogen‐activated protein kinase kinases (MEK1/2) degrader as a template, a series of 132 novel PROTAC‐like molecules is synthesized using solid‐phase Ugi reaction. These compounds are further characterized using various methods, including matrix‐assisted laser desorption ionization mass spectrometry (MALDI‐MS) imaging, while consuming only a few milligrams of starting materials in total. Furthermore, the feasibility of culturing cancer cells on the modified spots and quantifying the effect of MEK suppression is demonstrated. The miniaturized synthesis platform lays a foundation for high‐throughput in situ biological screening of potent PROTACs for potential anticancer activity and offers the potential for accelerating the drug discovery process by integrating miniaturized synthesis and biological steps on the same array.

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“…Additionally, they independently discovered the binding of ATRX to all components of the MRN complex, which plays a major role in double-stranded DNA damage repair, such as at collapsed replication forks. More recent evidence identified FANCD2 as another binding partner of ATRX, which together with MRN forms a super-complex that protects against replication fork collapse 90 . Both ATRX and FANCD2 are independently recruited to stalled replication forks and together recruit CtIP to enable fork regression and restart.…”

Section: The Role Of Atrx In the Cell Cycle And Dna Damagementioning

confidence: 99%

“…As mentioned above X5050 only worked at high micromolar concentrations, which might limit its therapeutic applicability. However, this could be overcome by developing a PROTAC (i.e., a system to target a protein of interest for degradation) for X5050, since PROTACs have previously been shown to enhance the effectivity of many inhibitors 90 . In chapter 4 we also showed selective effectivity of both alisertib and THZ531 against ATRX -/-SK-N-AS clones, but not in our ATRX -/-GI-ME-N clones.…”

Section: Novel Targets In Combating Atrx Aberrant Neuroblastomamentioning

confidence: 99%

The role of ATRX in neuroblastoma

van Gerven

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Cancer is worldwide the number one cause of death among young children. A frequently occurring type of paediatric cancer is neuroblastoma, which arises in parasympathetic ganglia. A specific subgroup of neuroblastoma patients with high-risk disease is characterised by genetic aberrations in the chromatin remodeller ATRX. ATRX is responsible for the incorporation of the histone variant H3.3 at repetitive DNA. It is assumed that this function is important for genome stability. In neuroblastoma distinct mutations occur within the ATRX gene. However, an overview of all occurring mutations, their frequencies and their associations with patient and tumour characteristics was lacking. Therefore, I first focussed on generating an overview of the ATRX mutational landscape in neuroblastoma and all other types of paediatric cancer. To accomplish this, we determined the frequency of ATRX nonsense mutations, missense mutations, and multi-exon deletions (MEDs). This led us to the discovery that the latter occurred almost exclusively in neuroblastoma and that 70% of the ATRX aberrations in neuroblastoma are MEDs. Furthermore, we predicted that 75% of these MEDs are likely in-frame and result in the production of shorter protein products. Additionally, we discovered a slightly better overall survival for patients with ATRX missense mutations compared to the other mutation types. We also found that 11q deletions, which are independently associated with poor survival, co-occur more frequently with ATRX MEDs compared to the other ATRX mutation types or wild-type. Altogether, this suggests the existence of different ATRX sub-types within neuroblastoma. To investigate whether such different ATRX subtypes exist we generated multiple isogenic cell line models with distinct ATRX aberrations, namely knock-out, exon 2-10 MED and exon 2-13 MED models. On these models we conducted total RNA-sequencing and for our analysis we also included the RNA-sequencing data of eight neuroblastoma cell lines, including three with an ATRX MED, and data of nine neuroblastoma tumours, including two with an exon 2-10 MED. By comparing the gene expression against the ATRX wild-type cells we discovered in all ATRX mutant changes in the expression of genes involved in ribosome biogenesis and metabolism. We found reduced gene expression related to these processes in the ATRX exon 2-10 MEDs models, but in sharp contrast we observed increased expression in ATRX KO and ATRX exon 2-13 models. In this manner we confirmed the existence of distinct ATRX sub-types. Subsequently, we conducted drug screens and genome-wide CRISPR-Cas9 synthetic lethality screens on ATRX aberrant cells to discover fast implementable drugs or identify novel drug targets. By performing drug screens we discovered three drugs that showed effectivity against all neuroblastoma cell lines tested independent of the ATRX mutational status. Additionally, we discovered 541 and 376 potential synthetic lethal interactions for ATRX KO and ATRX MED, respectively, compared to ATRX-wildtype cells. These synthetic lethal interactions give hope for the future as they could potentially be used as novel therapeutic targets. Finally, I discuss the implications of our findings in relation to one another and to the current knowledge regarding ATRX, additionally I mention potential directions for future research.

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Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges

Cited by 8 publications

References 124 publications

Targeting Death-Associated Protein Kinases for Treatment of Human Diseases: Recent Advances and Future Directions

Targeting Death-Associated Protein Kinases for Treatment of Human Diseases: Recent Advances and Future Directions

High‐Throughput Miniaturized Synthesis of PROTAC‐Like Molecules

The role of ATRX in neuroblastoma

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