pladienolide-b and Neoplasms

Pladienolides, an emerging class of naturally occurring spliceosome modulators, exhibit interesting structural features, such as highly substituted 12-membered macrocycles and epoxide-containing diene side chains. The potential of pladienolides as anti-cancer agents is confirmed by H3B-8800, a synthetic analog of this natural product class, which is currently under Phase I clinical trials. Since its isolation in 2004 and the first total synthesis in 2007, a dozen total syntheses and synthetic approaches toward the pladienolide class have been reported to date. This review focuses on the eight completed total syntheses of naturally occurring pladienolides or their synthetic analogs, in addition to a synthetic approach to the main framework of the natural product.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biological Products; Epoxy Compounds; Humans; Macrolides; Neoplasms; Spliceosomes

A growing body of studies has documented the pathological influence of impaired alternative splicing (AS) events on numerous diseases, including cancer. In addition, the generation of alternatively spliced isoforms is frequently noted to result in drug resistance in many cancer therapies. To gain comprehensive insights into the impacts of AS events on cancer biology and therapeutic developments, this paper highlights recent findings regarding the therapeutic routes of targeting alternative-spliced isoforms and splicing regulators to treatment strategies for distinct cancers.

Topics: Adaptor Proteins, Signal Transducing; Alternative Splicing; Antineoplastic Agents; Carcinogenesis; Caspase 9; Cyclin D1; Cyclohexylamines; Epoxy Compounds; Humans; Macrolides; Neoplasm Proteins; Neoplasms; Nuclear Proteins; Oligonucleotides; Pyrans; RNA Splicing Factors; RNA, Messenger; Spiro Compounds; Spliceosomes; Tumor Suppressor Proteins

Natural products are an abundant source of anti cancer agents. They act as cytotoxic drugs, and inhibitors of apoptosis, transcription, cell proliferation and angiogenesis. While pathways targeted by natural products have been well studied, there is paucity of information about the in vivo molecular target/s of these compounds. This review summarizes some of the natural compounds for which the molecular targets, mechanism of action and structural basis of specificity have been well documented. These examples illustrate that 'off target' binding can be explained on the basis of diversity inherent to biomolecular interactions. There is enough evidence to suggest that natural compounds are potent and versatile warheads that can be optimized for a multi targeted therapeutic intervention in cancer.

Topics: Antineoplastic Agents; Benzamides; Biological Products; Cyclohexanes; Epoxy Compounds; Fatty Acids, Unsaturated; Flavonoids; Humans; Imatinib Mesylate; Macrolides; Neoplasms; Piperazines; Piperidines; Proteins; Pyrimidines; Sesquiterpenes

Abnormal pre-mRNA splicing regulation is common in cancer, but the effects of chemotherapy on this process remain unclear.. To evaluate the effect of chemotherapy on slicing regulation, we performed meta-analyses of previously published transcriptomic, proteomic, phosphoproteomic, and secretome datasets. Our findings were verified by LC-MS/MS, western blotting, immunofluorescence, and FACS analyses of multiple cancer cell lines treated with cisplatin and pladienolide B.. Our results revealed that different types of chemotherapy lead to similar changes in alternative splicing by inducing intron retention in multiple genes. To determine the mechanism underlying this effect, we analyzed gene expression in 101 cell lines affected by ɣ-irradiation, hypoxia, and 10 various chemotherapeutic drugs. Strikingly, оnly genes involved in the cell cycle and pre-mRNA splicing regulation were changed in a similar manner in all 335 tested samples regardless of stress stimuli. We revealed significant downregulation of gene expression levels in these two pathways, which could be explained by the observed decrease in splicing efficiency and global intron retention. We showed that the levels of active spliceosomal proteins might be further post-translationally decreased by phosphorylation and export into the extracellular space. To further explore these bioinformatics findings, we performed proteomic analysis of cisplatin-treated ovarian cancer cells. Finally, we demonstrated that the splicing inhibitor pladienolide B impairs the cellular response to DNA damage and significantly increases the sensitivity of cancer cells to chemotherapy.. Decreased splicing efficiency and global intron retention is a novel stress response mechanism that may promote survival of malignant cells following therapy. We found that this mechanism can be inhibited by pladienolide B, which significantly increases the sensitivity of cancer cells to cisplatin which makes it a good candidate drug for improving the efficiency of cancer therapy.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cluster Analysis; DNA Damage; Down-Regulation; Epoxy Compounds; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Introns; Macrolides; Neoplasms; Phosphorylation; Proteomics; RNA Precursors; RNA Splicing; RNA, Messenger; Spliceosomes; Stress, Physiological; Transcription Factors; Xenograft Model Antitumor Assays

Pladienolide B (PB) is a potent cancer cell growth inhibitor that targets the SF3B1 subunit of the spliceosome. There is considerable interest in the compound as a potential chemotherapeutic, as well as a tool to study SF3B1 function in splicing and cancer development. The molecular structure of PB, a bacterial natural product, contains a 12-member macrolide ring with an extended epoxide-containing side chain. Using a novel concise enantioselective synthesis, we created a series of PB structural analogs and the structurally related compound herboxidiene. We show that two methyl groups in the PB side chain, as well as a feature of the macrolide ring shared with herboxidiene, are required for splicing inhibition in vitro. Unexpectedly, we find that the epoxy group contributes only modestly to PB potency and is not absolutely necessary for activity. The orientations of at least two chiral centers off the macrolide ring have no effect on PB activity. Importantly, the ability of analogs to inhibit splicing in vitro directly correlated with their effects in a series of cellular assays. Those effects likely arise from inhibition of some, but not all, endogenous splicing events in cells, as previously reported for the structurally distinct SF3B1 inhibitor spliceostatin A. Together, our data support the idea that the impact of PB on cells is derived from its ability to impair the function of SF3B1 in splicing and also demonstrate that simplification of the PB scaffold is feasible.

Topics: Antineoplastic Agents; Epoxy Compounds; HeLa Cells; Humans; Macrolides; Neoplasm Proteins; Neoplasms; Phosphoproteins; Pyrans; Ribonucleoprotein, U2 Small Nuclear; RNA Splicing; RNA Splicing Factors; Spiro Compounds

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.

Topics: Animals; Antineoplastic Agents; Biological Factors; Cell Line, Tumor; Cell Proliferation; Chlorocebus aethiops; COS Cells; Drug Design; Drug Screening Assays, Antitumor; Epoxy Compounds; Humans; Macrolides; Mice; Models, Molecular; Molecular Conformation; Neoplasms; NIH 3T3 Cells; Pyrans; Spiro Compounds; Stereoisomerism