RESUMO
Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor-encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function, but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells. These killing effects of H3B-8800 are due to its direct interaction with the SF3b complex, as evidenced by loss of H3B-8800 activity in drug-resistant cells bearing mutations in genes encoding SF3b components. Although H3B-8800 modulates WT and mutant spliceosome activity, the preferential killing of spliceosome-mutant cells is due to retention of short, GC-rich introns, which are enriched for genes encoding spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.
Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/genética , Piperazinas/farmacologia , Piridinas/farmacologia , Splicing de RNA/genética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Spliceossomos/genética , Administração Oral , Animais , Sequência de Bases , Humanos , Íntrons/genética , Células K562 , Leucemia/genética , Leucemia/patologia , Camundongos , Mutação , Neoplasias/patologia , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Splicing de RNA/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Recurrent mutations in the spliceosome are observed in several human cancers, but their functional and therapeutic significance remains elusive. SF3B1, the most frequently mutated component of the spliceosome in cancer, is involved in the recognition of the branch point sequence (BPS) during selection of the 3' splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 3' ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wild-type SF3B1 and requires the canonical 3' ss to enable aberrant splicing during the second step. Approximately 50% of the aberrantly spliced mRNAs are subjected to nonsense-mediated decay resulting in downregulation of gene and protein expression. These findings ascribe functional significance to the consequences of SF3B1 mutations in cancer.
Assuntos
Processamento Alternativo , Mutação , Neoplasias/genética , Fosfoproteínas/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Alelos , Sequência de Aminoácidos , Sequência de Bases , Células HEK293 , Humanos , Dados de Sequência Molecular , Taxa de Mutação , Degradação do RNAm Mediada por Códon sem Sentido , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Fatores de Processamento de RNA , Ribonucleoproteína Nuclear Pequena U2/química , Ribonucleoproteína Nuclear Pequena U2/metabolismoRESUMO
The total synthesis of kalihinol C, a bis-isonitrile marine diterpenoid isolated from Acanthella sp., is reported. The decalin framework was established via an intramolecular Diels-Alder cycloaddition and subsequently functionalized through a series of substrate-controlled diastereoselective transformations to install the tertiary isonitrile, beta-hydroxy isonitrile, and pendant tetrahydrofuranyl ring.
Assuntos
Antimaláricos/síntese química , Diterpenos/síntese química , Nitrilas/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Nitrilas/químicaRESUMO
A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.