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Luisa Vigevani, André Gohr, Thomas Webb, Manuel Irimia, Juan Valcárcel
Several splicing-modulating compounds, including Sudemycins and Spliceostatin A, display anti-tumor properties. Combining transcriptome, bioinformatic and mutagenesis analyses, we delineate sequence determinants of the differential sensitivity of 3' splice sites to these drugs. Sequences 5' from the branch point (BP) region strongly influence drug sensitivity, with additional functional BPs reducing, and BP-like sequences allowing, drug responses. Drug-induced retained introns are typically shorter, displaying higher GC content and weaker polypyrimidine-tracts and BPs...
December 13, 2017: Nature Communications
Morgan Thurman, Jacob van Doorn, Barbara Danzer, Thomas R Webb, Stefan Stamm
OBJECTIVE: The aim of the study was to define pharmacodynamic markers for sudemycin D6, an experimental cancer drug that changes alternative splicing in human blood. METHODS: Blood samples from 12 donors were incubated with sudemycin D6 for up to 24 hours, and at several time points total RNA from lymphocytes was prepared and the pre-messenger RNA (mRNA) splicing patterns were analyzed with reverse transcription-polymerase chain reaction. RESULTS: Similar to immortalized cells, blood lymphocytes change alternative splicing due to sudemycin D6 treatment...
2017: Biomarker Insights
Kamil Makowski, Luisa Vigevani, Fernando Albericio, Juan Valcárcel, Mercedes Álvarez
Important links exist between the process of pre-mRNA splicing and cancer, as illustrated by the frequent mutation of splicing factors in tumors and the emergence of various families of antitumor drugs that target components of the splicing machinery, notably SF3B1, a protein subunit of spliceosomal U2 small nuclear ribonucleoprotein particle (snRNP). Sudemycins are synthetic compounds that harbor a pharmacophore common to various classes of splicing inhibitors. Here, we describe the synthesis and functional characterization of novel sudemycin analogues that functionally probe key chemical groups within this pharmacophore...
January 20, 2017: ACS Chemical Biology
Cara Lunn Shirai, Brian S White, Manorama Tripathi, Roberto Tapia, James N Ley, Matthew Ndonwi, Sanghyun Kim, Jin Shao, Alexa Carver, Borja Saez, Robert S Fulton, Catrina Fronick, Michelle O'Laughlin, Chandraiah Lagisetti, Thomas R Webb, Timothy A Graubert, Matthew J Walter
Somatic mutations in spliceosome genes are detectable in ∼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls...
January 9, 2017: Nature Communications
Yihui Shi, Jaehyeon Park, Chandraiah Lagisetti, Wei Zhou, Lidia C Sambucetti, Thomas R Webb
The splicing of pre-mRNA is a critical process in normal cells and is deregulated in cancer. Compounds that modulate this process have recently been shown to target a specific vulnerability in tumors. We have developed a novel cell-based assay that specifically activates luciferase in cells exposed to SF3B1 targeted compounds, such as sudemycin D6. This assay was used to screen a combined collection of approved drugs and bioactive compounds. This screening approach identified several active hits, the most potent of which were CGP-74514A and aminopurvalanol A, both have been reported to be cyclin-dependent kinases (CDKs) inhibitors...
February 1, 2017: Bioorganic & Medicinal Chemistry Letters
Ning Zhang, Ling He, Helin Feng, Yan Kong, Jin Wang, Jinming Zhang
No abstract text is available yet for this article.
December 2016: Neurochemical Research
Yihui Shi, Amanda S Joyner, William Shadrick, Gustavo Palacios, Chandraiah Lagisetti, Philip M Potter, Lidia C Sambucetti, Stefan Stamm, Thomas R Webb
The spliceosome has recently emerged as a new target for cancer chemotherapy and novel antitumor spliceosome targeted agents are under development. Here, we describe two types of novel pharmacodynamic assays that facilitate drug discovery and development of this intriguing class of innovative therapeutics; the first assay is useful for preclinical optimization of small-molecule agents that target the SF3B1 spliceosomal protein in animals, the second assay is an ex vivo validated, gel-based assay for the measurement of drug exposure in human leukocytes...
August 2015: Pharmacology Research & Perspectives
Sílvia Xargay-Torrent, Mónica López-Guerra, Laia Rosich, Arnau Montraveta, Jocabed Roldán, Vanina Rodríguez, Neus Villamor, Marta Aymerich, Chandraiah Lagisetti, Thomas R Webb, Carlos López-Otín, Elias Campo, Dolors Colomer
Mutations or deregulated expression of the components of the spliceosome can influence the splicing pattern of several genes and contribute to the development of tumors. In this context, we report that the spliceosome modulator sudemycin induces selective cytotoxicity in primary chronic lymphocytic leukemia (CLL) cells when compared with healthy lymphocytes and tumor cells from other B-lymphoid malignancies, with a slight bias for CLL cases with mutations in spliceosome-RNA processing machinery. Consistently, sudemycin exhibits considerable antitumor activity in NOD/SCID/IL2Rγ-/- (NSG) mice engrafted with primary cells from CLL patients...
September 8, 2015: Oncotarget
Morgan Thénoz, Céline Vernin, Hussein Mortada, Maroun Karam, Christiane Pinatel, Antoine Gessain, Thomas R Webb, Didier Auboeuf, Eric Wattel, Franck Mortreux
BACKGROUND: Reprogramming cellular gene transcription sustains HTLV-1 viral persistence that ultimately leads to the development of adult T-cell leukemia/lymphoma (ATLL). We hypothesized that besides these quantitative transcriptional effects, HTLV-1 qualitatively modifies the pattern of cellular gene expression. RESULTS: Exon expression analysis shows that patients' untransformed and malignant HTLV-1(+) CD4(+) T-cells exhibit multiple alternate exon usage (AEU) events...
2014: Retrovirology
Paolo Convertini, Manli Shen, Philip M Potter, Gustavo Palacios, Chandraiah Lagisetti, Pierre de la Grange, Craig Horbinski, Yvonne N Fondufe-Mittendorf, Thomas R Webb, Stefan Stamm
Sudemycin E is an analog of the pre-messenger RNA splicing modulator FR901464 and its derivative spliceostatin A. Sudemycin E causes the death of cancer cells through an unknown mechanism. We found that similar to spliceostatin A, sudemycin E binds to the U2 small nuclear ribonucleoprotein (snRNP) component SF3B1. Native chromatin immunoprecipitations showed that U2 snRNPs physically interact with nucleosomes. Sudemycin E induces a dissociation of the U2 snRNPs and decreases their interaction with nucleosomes...
April 2014: Nucleic Acids Research
Chandraiah Lagisetti, Gustavo Palacios, Tinopiwa Goronga, Burgess Freeman, William Caufield, Thomas R Webb
The spliceosome regulates pre-mRNA splicing, which is a critical process in normal mammalian cells. Recently, recurrent mutations in numerous spliceosomal proteins have been associated with a number of cancers. Previously, natural product antitumor agents have been shown to interact with one of the proteins that is subject to recurrent mutations (SF3B1). We report the optimization of a class of tumor-selective spliceosome modulators that demonstrate significant in vivo antitumor activity. This optimization culminated in the discovery of sudemycin D6, which shows potent cytotoxic activity in the melanoma line SK-MEL-2 (IC50 = 39 nM) and other tumor cell lines, including JeKo-1 (IC50 = 22 nM), HeLa (IC50 = 50 nM), and SK-N-AS (IC50 = 81 nM)...
December 27, 2013: Journal of Medicinal Chemistry
Tinopiwa Goronga, Vincent A Boyd, Chandraiah Lagisetti, Cynthia Jeffries, Thomas R Webb
A set of novel antitumor agents (the sudemycins) has recently been described that are analogs of the natural product FR901464. We report the radiosynthesis of two of these antitumor drug lead compounds, using a three step procedure: (1) ester hydrolysis, (2) Lindlar's catalyst/tritium gas to give a (S,Z)-4-acetoxypent-2-enoic acid derivative, and finally (3) amide bond formation. These labeled analogs are useful in developing a better understanding of the pharmacological properties of this new class of therapeutic lead compounds...
September 2011: Applied Radiation and Isotopes
Liying Fan, Chandraiah Lagisetti, Carol C Edwards, Thomas R Webb, Philip M Potter
Two unrelated bacterial natural products, FR901464 and pladienolide B, have previously been shown to have significant antitumor activity in vivo. These compounds target the SF3b subunit of the spliceosome, with a derivative of pladienolide (E7107) entering clinical trials for cancer. However, due to the structural complexity of these molecules, their research and development has been significantly constrained. We have generated a set of novel analogues (Sudemycins) that possess the pharmacophore that is common to FR901464 and pladienolide, via a flexible enantioselective route, which allows for the production of gram quantities of drug...
June 17, 2011: ACS Chemical Biology
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