Profiling the Binding Activities of Peptides and Inhibitors to the U2 Auxiliary Factor Homology Motif (UHM) Domains

Yuan, Xinrui; Howie, Kathryn L.; Sabzvar, Mona Kazemi; Chinnaswamy, Krishnapriya; Stuckey, Jeanne A.; Yang, Chao‐Yie

doi:10.1021/acsmedchemlett.2c00537

Cited by 4 publications

(10 citation statements)

References 41 publications

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“…65 Yet, achieving specificity remains challenging, as demonstrated by limited selectivity of UHMCP1 and phenothiazine derivatives for target UHMs. 66,67 Future studies aim to optimize these molecules for specificity and safety. Alternatively, it should be noted that UHM-containing proteins can also be targeted on distinct regions.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study, the binding activity profiles of UHMCP1 derivatives were determined using binding assays. 66 Unmodified UHMCP1 showed IC 50 values of 74.85 μM for SPF45-UHM, 159.35 μM for RBM39-UHM, 175.61 μM for PUF60-UHM and 239.9 μM for U2AF35-UHM, highlighting the limited selectivity of UHMCP1 to target UHM domains. 66…”

Section: Small Molecules Targeting the Spliceosomementioning

confidence: 92%

“…66 Unmodified UHMCP1 showed IC 50 values of 74.85 μM for SPF45-UHM, 159.35 μM for RBM39-UHM, 175.61 μM for PUF60-UHM and 239.9 μM for U2AF35-UHM, highlighting the limited selectivity of UHMCP1 to target UHM domains. 66…”

Section: Small Molecules Targeting the Spliceosomementioning

confidence: 92%

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Small molecules modulating RNA splicing: a review of targets and future perspectives

Bouton,

Ecoutin,

Malard

et al. 2024

RSC Med. Chem.

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Section: Discussionmentioning

confidence: 99%

Section: Small Molecules Targeting the Spliceosomementioning

confidence: 92%

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Small molecules modulating RNA splicing: a review of targets and future perspectives

Bouton,

Ecoutin,

Malard

et al. 2024

RSC Med. Chem.

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“…S1). 42 To discover hits, we screened the CCG fragment library from University of Michigan against the U2AF1-UHM domain using the Thermal Shift Assay (TSA). An initial single concentration screening at 200 μM led to identify 149 compounds that gave positive shifts of the melting temperature (DTm) in U2AF1-UHM.…”

Section: Identification Of Sf1-8 From Fragment Library Screening Agai...mentioning

confidence: 99%

Comprehensive Analyses of the Effects of the Small-Molecule Inhibitor of the UHM Domain in the Splicing Factor U2AF1 in Leukemia Cells

Yang,

Yuan,

Sabzvar

et al. 2024

Preprint

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Mutations in RNA splicing factor genes including SF3B1, U2AF1, SRSF2, and ZRSR2 have been reported to contribute to development of myeloid neoplasms including myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML). Chemical tools targeting cells carrying these mutant genes remain limited and underdeveloped. Among the four proteins, mutant U2AF1 (U2AF1mut) acquires an altered 3’ splice site selection preference and co-operates with the wild-type U2AF1 (U2AF1wt) to change various gene isoform patterns to support MDS cells survival and proliferation. U2AF1 mutations in MDS cells are always heterozygous and the cell viability is reduced when exposed to additional insult affecting U2AF1wt function. To investigate if the pharmacological inhibition of U2AF1wt function can provoke drug-induced vulnerability of cells harboring U2AF1mut, we conducted a fragment-based library screening campaign to discover compounds targeting the U2AF homology domain (UHM) in U2AF1 that is required for the formation of the U2AF1/U2AF2 complex to define the 3' splice site. The most promising hit (SF1-8) selectively inhibited growth of leukemia cell lines overexpressingU2AF1mut and human primary MDS cells carrying U2AF1mut. RNA-seq analysis of K562-U2AF1mut following treatment with SF1-8 further revealed alteration of isoform patterns for a set of proteins that impair or rescue pathways associated with endocytosis, intracellular vesicle transport, and secretion. Our data suggested that further optimization of SF1-8 is warranted to obtain chemical probes that can be used to evaluate the therapeutic concept of inducing lethality to U2AF1mut cells by inhibiting the U2AF1wt protein.

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“…Some splicing factors contain an atypical RNA-recognition domain (U2AF homology motif [UHM]) that can interact with U2AF ligand motifs (ULMs) in proteins, which plays a role in regulating RNA splicing. Several RBPs, such as RBM39 and U2AF2, contain a UHM for protein-protein interactions [134,135]. Compared with RNAbinding domains, this domain is more druggable because of the presence of a hydrophobic pocket [136].…”

Section: Small Molecules Affecting the Dynamics Of Rbpsmentioning

confidence: 99%

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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Profiling the Binding Activities of Peptides and Inhibitors to the U2 Auxiliary Factor Homology Motif (UHM) Domains

Cited by 4 publications

References 41 publications

Small molecules modulating RNA splicing: a review of targets and future perspectives

Small molecules modulating RNA splicing: a review of targets and future perspectives

Comprehensive Analyses of the Effects of the Small-Molecule Inhibitor of the UHM Domain in the Splicing Factor U2AF1 in Leukemia Cells

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

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