更新于：2024-11-01

PHF5A x SF3B1

更新于：2024-11-01

基本信息

关联

项与 PHF5A x SF3B1 相关的药物

WX-02-23

靶点

PHF5A x SF3B1

作用机制

PHF5A modulators [+1]

在研机构

The Rockefeller University

原研机构

The Rockefeller University

在研适应症

血液肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PHF5A x SF3B1 相关的临床结果

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100 项与 PHF5A x SF3B1 相关的转化医学

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0 项与 PHF5A x SF3B1 相关的专利（医药）

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项与 PHF5A x SF3B1 相关的文献（医药）

2023-11-09·Journal of Medicinal Chemistry1区 · 医学

Synthesis and Conformational Analysis of FR901464-Based RNA Splicing Modulators and Their Synergism in Drug-Resistant Cancers

1区 · 医学

Article

作者: Schmitz, John C. ; Koide, Kazunori ; Markaj, Paulo L. ; Bressin, Robert K. ; Beard, Jacob P.

FR901464 is a cytotoxic natural product that binds splicing factor 3B subunit 1 (SF3B1) and PHD finger protein 5A (PHF5A), the components of the human spliceosome. The amide-containing tetrahydropyran ring binds SF3B1, and it remains unclear how the substituents on the ring contribute to the binding. Here, we synthesized meayamycin D, an analogue of FR901464, and three additional analogues to probe the conformation through methyl scanning. We discovered that the amide-containing tetrahydropyran ring assumes only one of the two possible chair conformations and that methylation of the nitrogen distorts the chair form, dramatically reducing cytotoxicity. Meayamycin D induced alternative splicing of MCL-1, showed strong synergism with venetoclax in drug-resistant lung cancer cells, and was cancer-specific over normal cells. Meayamycin D incorporates an alkyl ether and shows a long half-life in mouse plasma. The characteristics of meayamycin D may provide an approach to designing other bioactive L-shaped molecules.

2020-05-26·Journal of Chemical Information and Modeling

Exploiting Cryo-EM Structural Information and All-Atom Simulations To Decrypt the Molecular Mechanism of Splicing Modulators

Article

作者: Borišek, Jure ; Saltalamacchia, Andrea ; Spinello, Angelo ; Magistrato, Alessandra

Splicing modulators (SMs) pladienolides, herboxidienes, and spliceostatins exert their antitumor activity by altering the ability of SF3B1 and PHF5A proteins, components of SF3b splicing factor, to recognize distinct intron branching point sequences, thus finely calibrating constitutive/alternative/aberrant splicing of pre-mRNA. Here, by exploiting structural information obtained from cryo-EM data, and by performing multiple μs-long all-atom simulations of SF3b in apo form and in complex with selected SMs, we disclose how these latter seep into the narrow slit at the SF3B1/PHF5A protein interface. This locks the intrinsic open/closed conformational transitions of SFB1's solenoidal structure into the open state. As a result, SMs prevent the formation of a closed/intron-loaded conformation of the SF3B1 protein by decreasing the internal SF3B1 cross-correlation and reducing SF3B1's functional plasticity. We further compellingly support the proposition that SMs' action exceeds a purely competitive inhibition. Indeed, our simulations also demonstrate that the introduction of recurrent drug resistance/sensitizing mutations in SF3B1 or PHF5A, besides affecting the binding affinity of SMs, likewise influence the functional dynamics of SF3B1. This knowledge clarifies the molecular terms of SF3b modulation by small-molecules, fostering the rational-based discovery of drugs tackling distinct cancer types resulting from dysregulated splicing. This work also supports the coming of age usage of cryo-EM structural data in forthcoming drug-discovery studies.

2018-10-01·Life Science Alliance3区 · 生物学

MBNL1 alternative splicing isoforms play opposing roles in cancer

3区 · 生物学

ArticleOA

作者: Teo, Winnie Koon Lay ; Aw, Joey ; Tabaglio, Tommaso ; Sobczak, Krzysztof ; Guccione, Ernesto ; Ho, Jessica ; Tan, Damien ; Goy, Pierre Alexis ; Cywoniuk, Piotr ; Pavesi, Andrea ; Wollmann, Heike ; Low, Diana Hp ; Wee, Dave Keng Boon

The extent of and the oncogenic role played by alternative splicing (AS) in cancer are well documented. Nonetheless, only few studies have attempted to dissect individual gene function at an isoform level. Here, we focus on the AS of splicing factors during prostate cancer progression, as these factors are known to undergo extensive AS and have the potential to affect hundreds of downstream genes. We identified exon 7 (ex7) in the MBNL1 (Muscleblind-like 1) transcript as being the most differentially included exon in cancer, both in cell lines and in patients' samples. In contrast, MBNL1 overall expression was down-regulated, consistently with its described role as a tumor suppressor. This observation holds true in the majority of cancer types analyzed. We first identified components associated to the U2 splicing complex (SF3B1, SF3A1, and PHF5A) as required for efficient ex7 inclusion and we confirmed that this exon is fundamental for MBNL1 protein homodimerization. We next used splice-switching antisense oligonucleotides (AONs) or siRNAs to compare the effect of MBNL1 splicing isoform switching with knockdown. We report that whereas the absence of MBNL1 is tolerated in cancer cells, the expression of isoforms lacking ex7 (MBNL1 Δex7) induces DNA damage and inhibits cell viability and migration, acting as dominant negative proteins. Our data demonstrate the importance of studying gene function at the level of alternative spliced isoforms and support our conclusion that MBNL1 Δex7 proteins are antisurvival factors with a defined tumor suppressive role that cancer cells tend to down-regulate in favor of MBNL +ex7 isoforms.