Identification and selectivity profiling of small-molecule degraders via multi-omics approaches

Scholes, Natalie S.; Mayor‐Ruiz, Cristina; Ciulli, Alessio

doi:10.1016/j.chembiol.2021.03.007

Cited by 41 publications

(32 citation statements)

References 101 publications

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“…To effectively capitalize on this synthetic lethality therapeutically, it will be necessary to develop selective degraders that only target one paralog or the other, thereby avoiding the toxicity associated with combined HDAC1/2 loss of function. Fortunately, it has been well demonstrated that PROTACs can achieve greater selectivity than their parental compounds, with multiple examples now of degraders that differentiate between two highly similar paralogs 64 . It may therefore be possible to develop paralog-selective degraders from ligands that bind both HDAC1 and HDAC2.…”

Section: Discussionmentioning

confidence: 99%

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

Zhang

Remillard

Onubogu

et al. 2022

Preprint

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Histone deacetylases (HDACs) have been widely pursued as targets for anti-cancer therapeutics. However, many of these targets are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between HDAC1 and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.

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Section: Discussionmentioning

confidence: 99%

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

Zhang

Remillard

Onubogu

et al. 2022

Preprint

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“…Recent findings derived from integrated multi-omics approaches include predictors of clinical response, identification of novel potential drug targets, profiling of compounds and mechanisms leading to drug resistance in different tumor types, and discovery of processes underlying cell plasticity [ 254 , 255 , 256 , 257 ]. This is further complemented by recent advances in medical imagery, where the reliability of pathologic assessment has been much increased by refined molecular imaging techniques, and also by artificial intelligence and machine learning [ 224 , 244 , 258 ].…”

Section: Discussionmentioning

confidence: 99%

From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

Nevedomskaya

Haendler

2022

IJMS

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Cancer arises following alterations at different cellular levels, including genetic and epigenetic modifications, transcription and translation dysregulation, as well as metabolic variations. High-throughput omics technologies that allow one to identify and quantify processes involved in these changes are now available and have been instrumental in generating a wealth of steadily increasing data from patient tumors, liquid biopsies, and from tumor models. Extensive investigation and integration of these data have led to new biological insights into the origin and development of multiple cancer types and helped to unravel the molecular networks underlying this complex pathology. The comprehensive and quantitative analysis of a molecule class in a biological sample is named omics and large-scale omics studies addressing different prostate cancer stages have been performed in recent years. Prostate tumors represent the second leading cancer type and a prevalent cause of cancer death in men worldwide. It is a very heterogenous disease so that evaluating inter- and intra-tumor differences will be essential for a precise insight into disease development and plasticity, but also for the development of personalized therapies. There is ample evidence for the key role of the androgen receptor, a steroid hormone-activated transcription factor, in driving early and late stages of the disease, and this led to the development and approval of drugs addressing diverse targets along this pathway. Early genomic and transcriptomic studies have allowed one to determine the genes involved in prostate cancer and regulated by androgen signaling or other tumor-relevant signaling pathways. More recently, they have been supplemented by epigenomic, cistromic, proteomic and metabolomic analyses, thus, increasing our knowledge on the intricate mechanisms involved, the various levels of regulation and their interplay. The comprehensive investigation of these omics approaches and their integration into multi-omics analyses have led to a much deeper understanding of the molecular pathways involved in prostate cancer progression, and in response and resistance to therapies. This brings the hope that novel vulnerabilities will be identified, that existing therapies will be more beneficial by targeting the patient population likely to respond best, and that bespoke treatments with increased efficacy will be available soon.

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“…It provides functional information in a scalable fashion and in the context of a cellular environment involving full-length and native protein components. For E3 ligases lacking structural data, like many of the ligases recently discovered to be amenable for TPD 49 , a structurally informed design of variant libraries, as well as a mechanistic interpretation of functional consequences revealed by DSM, will arguably be more challenging. However, protein structure prediction and ternary complex modeling could offer insights, particularly in cases where the degrader binding site on the E3 could be mapped 50 .…”

Section: Discussionmentioning

confidence: 99%

Charting functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders

Hanzl

Casement

Imrichová

et al. 2022

Preprint

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Targeted protein degradation is a new pharmacologic paradigm established by drugs that recruit target proteins to E3 ubiquitin ligases via a ternary ligase-degrader-target complex. Based on the structure of the degrader and the neosubstrate, different E3 ligase interfaces are critically involved in this process, thus forming defined functional hotspots. Understanding disruptive mutations in functional hotspots informs on the architecture of the underlying assembly, and highlights residues prone to cause drug resistance. Until now, their identification was driven by structural methods with limited scalability. Here, we employ haploid genetics to show that hotspot mutations cluster in the substrate receptors of the hijacked ligases and find that type and frequency of mutations are shaped by the essentiality of the harnessed ligase. Intersection with deep mutational scanning data revealed hotspots that are either conserved, or specific for chemically distinct degraders or recruited neosubstrates. Biophysical and structural validation suggest that hotspot mutations frequently converge on altered ternary complex assembly. Moreover, we identified and validated hotspots mutated in patients that relapse from degrader treatment. In sum, we present a fast and experimentally widely accessible methodology that empowers the characterization of small-molecule degraders and informs on associated resistance mechanisms.

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Identification and selectivity profiling of small-molecule degraders via multi-omics approaches

Cited by 41 publications

References 101 publications

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

Charting functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders

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