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Dive into the research topics where Thomas R. Webb is active.

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Featured researches published by Thomas R. Webb.


ACS Chemical Biology | 2011

Sudemycins, novel small molecule analogues of FR901464, induce alternative gene splicing

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. These compounds demonstrate cytotoxicity toward human tumor cell lines in culture and exhibit antitumor activity in a xenograft model. Here, we present evidence that Sudemycins are potent modulators of alternative splicing in human cells, both of endogenous genes and from minigene constructs. Furthermore, levels of alternative splicing are increased in tumor cells relative to normal cells, and these modifications can be observed in human tumor xenografts in vivo following exposure of animals to the drug. In addition, the change in the splicing pattern observed with the Sudemycins are similar to that observed with Spliceostatin A, a molecule known to interact with the SF3b subunit of the spliceosome. Hence, we conclude that Sudemycins can regulate the production of alternatively spliced RNA transcripts and these alterations are more prevalent in tumors, as compared to normal cells, following drug exposure. These studies suggest that modulation of alternative splicing may play a role in the antitumor activity of this class of agents.


Journal of Medicinal Chemistry | 2009

Synthetic mRNA splicing modulator compounds with in vivo antitumor activity.

Chandraiah Lagisetti; Alan Pourpak; Tinopiwa Goronga; Qin Jiang; Xiaoli Cui; Judith Hyle; Jill M. Lahti; Stephan W. Morris; Thomas R. Webb

We report our progress on the development of new synthetic anticancer lead compounds that modulate the splicing of mRNA. We also report the synthesis and evaluation of new biologically active ester and carbamate analogues. Further, we describe initial animal studies demonstrating the antitumor efficacy of compound 5 in vivo. Additionally, we report the enantioselective and diastereospecific synthesis of a new 1,3-dioxane series of active analogues. We confirm that compound 5 inhibits the splicing of mRNA in cell-free nuclear extracts and in a cell-based dual-reporter mRNA splicing assay. In summary, we have developed totally synthetic novel spliceosome modulators as therapeutic lead compounds for a number of highly aggressive cancers. Future efforts will be directed toward the more complete optimization of these compounds as potential human therapeutics.


Journal of Medicinal Chemistry | 2008

Antitumor compounds based on a natural product consensus pharmacophore.

Chandraiah Lagisetti; Alan Pourpak; Qin Jiang; Xiaoli Cui; Tinopiwa Goronga; Stephan W. Morris; Thomas R. Webb

We report the design and highly enantioselective synthesis of a potent analogue of the spliceosome inhibitor FR901464, based on a non-natural product scaffold. The design of this compound was facilitated by a pharmacophore hypothesis that assumed key interaction types that are common to FR901464 and an otherwise unrelated natural product (pladienolide). The synthesis allows for the preparation of numerous novel analogues. We present results on the in vitro activity for this compound against several tumor cell lines.


ACS Chemical Biology | 2014

Pre-mRNA splicing-modulatory pharmacophores: The total synthesis of herboxidiene, a pladienolide-herboxidiene hybrid analog and related derivatives

Chandraiah Lagisetti; Maria V. Yermolina; Lalit Kumar Sharma; Gustavo Palacios; Brett J. Prigaro; Thomas R. Webb

Herboxidiene is a natural product that has previously been shown to exhibit antitumor activity by targeting the spliceosome. This activity makes herboxidiene a valuable starting point for the development of anticancer drugs. Here, we report an improved enantioselective synthesis of herboxidiene and the first report of its biologically active totally synthetic analog: 6-norherboxidiene. The synthesis of the tetrahydropyran moiety utilizes the novel application of inverse electron-demand Diels-Alder chemistry and the Ferrier-type rearrangement as key steps. We report, for the first time, cytotoxicity IC50s for synthetic herboxidiene and analogs in human tumor cell lines. We have also demonstrated that synthetic herboxidiene and its analogs can potently modulate the alternate splicing of MDM-2 pre-mRNA.


Journal of Medicinal Chemistry | 2013

Optimization of Antitumor Modulators of Pre-mRNA Splicing

Chandraiah Lagisetti; Gustavo Palacios; Tinopiwa Goronga; Burgess B. 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). We also report improved processes for the synthesis of these compounds. Our work supports the idea that sudemycin D6 is worthy of further investigation as a novel preclinical anticancer agent with application in the treatment of numerous human cancers.


Tetrahedron Letters | 1994

Improved synthesis of arginine peptide aldehydes

Raymond Dagnino; Thomas R. Webb

Abstract An improved method for the synthesis of peptide argininals by the use of a new aldehyde protecting group (diphenylmethyl semicarbazide) is reported.


Journal of Medicinal Chemistry | 2010

Structure-Activity Relationships of Substituted 1-Pyridyl-2-Phenyl-1,2-Ethanediones: Potent, Selective Carboxylesterase Inhibitors

Brandon M. Young; Janice L. Hyatt; David C. Bouck; Taosheng Chen; Parimala Hanumesh; Jeanine Price; Vincent A. Boyd; Philip M. Potter; Thomas R. Webb

Inhibition of intestinal carboxylesterases may allow modification of the pharmacokinetics/pharmacodynamic profile of existing drugs by altering half-life or toxicity. Since previously identified diarylethane-1,2-dione inhibitors are decidedly hydrophobic, a modified dione scaffold was designed and elaborated into a >300 member library, which was subsequently screened to establish the SAR for esterase inhibition. This allowed the identification of single digit nanomolar hiCE inhibitors that showed improvement in selectivity and measured solubility.


Journal of Chemical Information and Modeling | 2008

Generation of New Synthetic Scaffolds Using Framework Libraries Selected and Refined via Medicinal Chemist Synthetic Expertise

Thomas R. Webb; Ruben E. Venegas; Jian Wang; Alain Deschenes

With the expansion in the application of library methods in medicinal chemistry and chemical biology there is a growing need for improved technology for the design of novel templates that are well suited for the synthesis of libraries targeted toward specific subsets of protein families. In this report, we delineate an improved stepwise general method that is well suited for this purpose. This process uses virtual framework libraries to identify frameworks that rigidly match specific aspects of a ligands bioactive conformation. The resulting frameworks can then be ranked and sequentially modified by a combination of computational scripts and human derived expertise, in order to develop rational proposals for new combinatorial templates or new sets of potential ligands.


Tetrahedron Letters | 1993

Facile determination of the Optical Purity of α-N-Boc-Amino Aldehydes

John Reiner; Raymond Dagnino; Erick Goldman; Thomas R. Webb

Abstract A facile 1 H NMR spectroscopic method is presented for the determination of the optical purity of α-amino aldehydes, via derivatization with optically pure semicarbazides.


RNA | 2018

Inhibition of SF3B1 by molecules targeting the spliceosome results in massive aberrant exon skipping

Gang Wu; Liying Fan; Michael Edmonson; Timothy I. Shaw; Kristy Boggs; John Easton; Michael Rusch; Thomas R. Webb; Jinghui Zhang; Philip M. Potter

The recent identification of compounds that interact with the spliceosome (sudemycins, spliceostatin A, and meayamycin) indicates that these molecules modulate aberrant splicing via SF3B1 inhibition. Through whole transcriptome sequencing, we have demonstrated that treatment of Rh18 cells with sudemycin leads to exon skipping as the predominant aberrant splicing event. This was also observed following reanalysis of published RNA-seq data sets derived from HeLa cells after spliceostatin A exposure. These results are in contrast to previous reports that indicate that intron retention was the major consequence of SF3B1 inhibition. Analysis of the exon junctions up-regulated by these small molecules indicated that these sequences were absent in annotated human genes, suggesting that aberrant splicing events yielded novel RNA transcripts. Interestingly, the length of preferred downstream exons was significantly longer than the skipped exons, although there was no difference between the lengths of introns flanking skipped exons. The reading frame of the aberrantly skipped exons maintained a ratio of 2:1:1, close to that of the cassette exons (3:1:1) present in naturally occurring isoforms, suggesting negative selection by the nonsense-mediated decay (NMD) machinery for out-of-frame transcripts. Accordingly, genes involved in NMD and RNAs encoding proteins involved in the splicing process were enriched in both data sets. Our findings, therefore, further elucidate the mechanisms by which SF3B1 inhibition modulates pre-mRNA splicing.

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Chandraiah Lagisetti

St. Jude Children's Research Hospital

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Chen Chen

Neurocrine Biosciences

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Philip M. Potter

St. Jude Children's Research Hospital

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Qin Jiang

St. Jude Children's Research Hospital

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