Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

Minuesa, Gerard; Albanese, Steven K.; Xie, Wei; Kazansky, Yaniv; Worroll, Daniel; Chow, Arthur; Schurer, Alexandra; Park, Sun-Mi; Rotsides, Christina Z.; Taggart, James; Rizzi, Andrea; Naden, Levi N.; Chou, Timothy; Gourkanti, Saroj; Cappel, Daniel; Passarelli, Maria C.; Fairchild, Lauren; Adura, Carolina; Glickman, J. Fraser; Schulman, Jessica; Famulare, Christopher; Patel, Minal; Eibl, Joseph K.; Ross, Gregory M.; Bhattacharya, Shibani; Tan, Derek S.; Leslie, Christina; Beuming, Thijs; Patel, Dinshaw J.; Goldgur, Yehuda; Chodera, John D.; Kharas, Michael G.

doi:10.1038/s41467-019-10523-3

Cited by 93 publications

(83 citation statements)

References 76 publications

(95 reference statements)

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“…The molecule showed weak binding (Kd ≈ 200 uM) towards SRSF2 and SYNCRIP, with nearly no binding to HuR. Strong structural and biochemical evidence suggests that Ro interacts with key residues at RRM1 of MSI2 [158]. Importantly, Ro significantly reduces the binding of MSI2-targeted mRNAs, including TGFBR1, c-MYC, SMAD3, and CDKN1A, in an RNA-IP assay.…”

Section: Hts Targeting Msi/rna Interactionsmentioning

confidence: 99%

“…Following this, one of the hits, Ro 08-2750 (Ro), showed an IC50 of 2.7 ± 0.4 µM to MSI2 in an FP assay. Ro bound directly to MSI2 (Kd = 12.3 ± 0.5 µM) in a MicroScale Thermophoresis (MST) assay [158]. The selectivity of Ro was tested against RBPs sharing conserved RRMs or similar mRNA targets with MSI2, by MST.…”

Section: Hts Targeting Msi/rna Interactionsmentioning

confidence: 99%

“…Importantly, Ro significantly reduces the binding of MSI2-targeted mRNAs, including TGFBR1, c-MYC, SMAD3, and CDKN1A, in an RNA-IP assay. It also inhibits the regulatory effects of MSI2 on the relevant proteins (TGFβR1, c-MYC, SMAD3, HOXA9, and P21) in human leukaemia cell lines [158]. Furthermore, Ro inhibits leukemogenesis in a murine myeloid leukaemia model in vivo, with a concomitant decrease of intracellular c-MYC levels [158].…”

Section: Hts Targeting Msi/rna Interactionsmentioning

confidence: 99%

“…It also inhibits the regulatory effects of MSI2 on the relevant proteins (TGFβR1, c-MYC, SMAD3, HOXA9, and P21) in human leukaemia cell lines [158]. Furthermore, Ro inhibits leukemogenesis in a murine myeloid leukaemia model in vivo, with a concomitant decrease of intracellular c-MYC levels [158]. The efficacy of Ro as an MSI2 inhibitor firmly supports the reliability of this HTS platform, where an artificial RNA oligo, designed by combining MSI binding motifs, is applied as the RNA probe.…”

Section: Hts Targeting Msi/rna Interactionsmentioning

confidence: 99%

“…Similarly, MSI1 has two separate RRMs structures [165,166]. MIS2 only has RRM1 structures published [158,167]. Most of the HuR/ARE disruptors target the RRM1-2, while the sole RRM3 ligand has shown weak interference with full-length HuR/ARE complex [122].…”

Section: Other Molecules Identified From Hts Targeting Msi/rna and Comentioning

confidence: 99%

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RNA-Targeted Therapies and High-Throughput Screening Methods

Zhu

Rooney

Michlewski

2020

IJMS

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RNA-binding proteins (RBPs) are involved in regulating all aspects of RNA metabolism, including processing, transport, translation, and degradation. Dysregulation of RNA metabolism is linked to a plethora of diseases, such as cancer, neurodegenerative diseases, and neuromuscular disorders. Recent years have seen a dramatic shift in the knowledge base, with RNA increasingly being recognised as an attractive target for precision medicine therapies. In this article, we are going to review current RNA-targeted therapies. Furthermore, we will scrutinise a range of drug discoveries targeting protein-RNA interactions. In particular, we will focus on the interplay between Lin28 and let-7, splicing regulatory proteins and survival motor neuron (SMN) pre-mRNA, as well as HuR, Musashi, proteins and their RNA targets. We will highlight the mechanisms RBPs utilise to modulate RNA metabolism and discuss current high-throughput screening strategies. This review provides evidence that we are entering a new era of RNA-targeted medicine.

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Section: Hts Targeting Msi/rna Interactionsmentioning

confidence: 99%

Section: Hts Targeting Msi/rna Interactionsmentioning

confidence: 99%

Section: Hts Targeting Msi/rna Interactionsmentioning

confidence: 99%

Section: Hts Targeting Msi/rna Interactionsmentioning

confidence: 99%

Section: Other Molecules Identified From Hts Targeting Msi/rna and Comentioning

confidence: 99%

See 3 more Smart Citations

RNA-Targeted Therapies and High-Throughput Screening Methods

Zhu

Rooney

Michlewski

2020

IJMS

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Targeting RNA‐binding proteins with small molecules: Perspectives, pitfalls and bifunctional molecules

Kang

2023

FEBS Letters

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RNA‐binding proteins (RBPs) play vital roles in organisms through binding with RNAs to regulate their functions. Small molecules affecting the function of RBPs have been developed, providing new avenues for drug discovery. Herein, we describe the perspectives on developing small molecule regulators of RBPs. The following types of small molecule modulators are of great interest in drug discovery: small molecules binding to RBPs to affect interactions with RNA molecules, bifunctional molecules binding to RNA or RBP to influence their interactions, and other types of molecules that affect the stability of RNA or RBPs. Moreover, we emphasize that the bifunctional molecules may play important roles in small molecule development to overcome the challenges encountered in the process of drug discovery.

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LncRNA LINC00942 promotes chemoresistance in gastric cancer by suppressing MSI2 degradation to enhance c‐Myc mRNA stability

Zhu

Zhou

et al. 2022

Clinical & Translational Med

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Background Chemoresistance to cisplatin (DDP) remains a major challenge in advanced gastric cancer (GC) treatment. Although accumulating evidence suggests an association between dysregulation of long non‐coding RNAs (lncRNAs) and chemoresistance, the regulatory functions and complexities of lncRNAs in modulating DDP‐based chemotherapy in GC remain under‐investigated. This study was designed to explore the critical chemoresistance‐related lncRNAs in GC and identify novel therapeutic targets for patients with chemoresistant GC. Methods Chemoresistance‐related lncRNAs were identified through microarray and verified through a quantitative real‐time polymerase chain reaction (qRT‐PCR). Proteins bound by lncRNAs were identified through a human proteome array and validated through RNA immunoprecipitation (RIP) and RNA pull‐down assays. Co‐immunoprecipitation and ubiquitination assays were performed to explore the molecular mechanisms of the Musashi2 (MSI2) post‐modification. The effects of LINC00942 (LNC942) and MSI2 on DDP‐based chemotherapy were investigated through MTS, apoptosis assays and xenograft tumour formation in vivo. Results LNC942 was found to be up‐regulated in chemoresistant GC cells, and its high expression was positively correlated with the poor prognosis of patients with GC. Functional studies indicated that LNC942 confers chemoresistance to GC cells by impairing apoptosis and inducing stemness. Mechanically, LNC942 up‐regulated the MSI2 expression by preventing its interaction with SCFβ‐TRCP E3 ubiquitin ligase, eventually inhibiting ubiquitination. Then, LNC942 stabilized c‐Myc mRNA in an N6‐methyladenosine (m6A)‐dependent manner. As a potential m6A recognition protein, MSI2 stabilized c‐Myc mRNA with m6A modifications. Moreover, inhibition of the LNC942‐MSI2‐c‐Myc axis was found to restore chemosensitivity both in vitro and in vivo. Conclusions These results uncover a chemoresistant accelerating function of LNC942 in GC, and disrupting the LNC942‐MSI2‐c‐Myc axis could be a novel therapeutic strategy for GC patients undergoing chemoresistance.

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Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

Cited by 93 publications

References 76 publications

RNA-Targeted Therapies and High-Throughput Screening Methods

RNA-Targeted Therapies and High-Throughput Screening Methods

Targeting RNA‐binding proteins with small molecules: Perspectives, pitfalls and bifunctional molecules

LncRNA LINC00942 promotes chemoresistance in gastric cancer by suppressing MSI2 degradation to enhance c‐Myc mRNA stability

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