peloruside A (RTA404) / Biogen - LARVOL DELTA

Endothelial cell Nrf2 controls neuroinflammation following a systemic insult. (PubMed, iScience) - "We found that peripheral inflammation caused infiltration of macrophages, microglial activation, and inflammatory reactive astrogliosis, all of which could be prevented by RTA-404, an activator of the transcription factor Nrf2 and close structural relative of the recently FDA-approved Nrf2 activator RTA-408 (omaveloxolone). Strikingly, the effects of RTA-404 on brain endothelial activation and downstream neuroinflammatory events were abolished by endothelial cell-specific Nrf2 deletion. This places endothelial cell Nrf2 as a peripherally accessible therapeutic target to reduce the CNS-adverse consequences of systemic inflammation."

Journal • CNS Disorders • Inflammation

Pelophen B is a non-taxoid binding microtubule-stabilizing agent with promising preclinical anticancer properties. (PubMed, Sci Rep) - "Pelophen B (PPH), a synthetic analog of peloruside A, stabilizes microtubules through interaction with a non-taxoid binding site of β-tubulin. Although, results induced by paclitaxel or PPH are concordant, PPH's unique microtubule binding mechanism enables PTX additivity and ensures overcoming PTX-induced resistance. In conclusion, PPH results in remarkable anti-cancer activity in a range of preclinical models supporting further clinical investigation of PPH as a therapeutic anticancer agent."

Journal • Preclinical • Breast Cancer • Oncology • Ovarian Cancer • Sarcoma • Solid Tumor

Chemical modulation of microtubule structure through the laulimalide/peloruside site. (PubMed, Structure) - "Among the compounds studied, we have found some showing low cytotoxicity and able to induce stabilization without compromising microtubule native structure. This opens the window of new applications for microtubule-stabilizing agents beyond cancer treatment."

Journal • Oncology • Solid Tumor

In silico to In vivo development of a polyherbal against Haemonchus contortus. (PubMed, Heliyon) - "In silico molecular docking and pharmacokinetic prediction studies were conducted with known bioactive molecules of these plants (palasonin, vinblastine, vincristine, betulinic acid and ursolic acid) against Glutamate Dehydrogenase (GDH) and tubulin molecules of the parasite...Albendazole bound to α-tubulin next to colchicine site whereas vinblastine is bound at the nearby laulimalide/peloruside site of the dimer...The in vitro studies demonstrated good dose dependent anthelmintic potential. Both the prototypes were quite efficacious in clearing the infection, keeping it to a minimal for more than 5 months, probably, through direct anthelmintic effect through GDH, tubulin depolymerization and uncoupling as well as indirectly through immunomodulation along with antioxidant and anti-inflammatory properties."

Journal • Preclinical • Immune Modulation • Immunology • Infectious Disease • Inflammation

Induction of Mitosis Delay and Apoptosis by CDDO-TFEA in Glioblastoma Multiforme. (PubMed, Front Pharmacol) - "Therefore, CDDO-TFEA may not only induce cell cycle G2/M arrest, it may also exert apoptosis in established GBM cells. CDDO-TFEA can inhibit proliferation, cell cycle progression and induce apoptosis in GBM cells in vitro, possibly though its inhibition of Cyclin B1, CDK1 expression, and Cyclin B1/CDK1 association and the promotion of CHK1 and CHK2 expression."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • CASP3 • CCNB1 • CDK1 • CHEK1 • CHEK2

RTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma. (PubMed, J Clin Med) - "In addition, the DNA damage checkpoint system seems also to be activated by RTA404. Taken together, RTA404 activated the DNA damage checkpoint system and induced apoptosis through intrinsic apoptotic pathways in established U87MG cells."

Journal • Brain Cancer • Glioma • Oncology • Solid Tumor • CASP3 • CHEK1 • CHEK2

On the Microtubule-Stabilizing Properties of a Tau Oligopeptide. (PubMed, J Chem Inf Model) - "Tau peptides strengthen the longitudinal protein-protein contacts within the MT lattice and exert a cooperative MT-stabilizing effect in MT complexes simultaneously bonded to taxol or peloruside A. Ser phosphorylation results in a larger peptide mobility, altered interaction profiles, and MT destabilization, which are in line with the loss of MT integrity resulting from the post-translational hyperphosphorylation of Tau. Our results shed light on the MT-stabilizing potential of Tau-mimetic peptides to act as novel neuroprotective agents targeting MTs."

Journal • Alzheimer's Disease • CNS Disorders

Therapeutic Potential of RTA 404 in Human Brain Malignant Glioma Cell Lines via Cell Cycle Arrest via p21/AKT Signaling. (PubMed, Biomed Res Int) - "An analysis of the p21/AKT expression suggested that RTA 404 may not only help prevent brain cancer but it may also exert antitumor activities in established GBM cells. RTA404 can inhibit proliferation, cell locomotion, cell cycle progression, and induce apoptosis in GBM cells in vitro, possibly through its inhibition of N-cadherin and E-cadherin expression via its inhibition of the AKT pathway."

Journal • Preclinical • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • CDH1 • CDKN1A

LC-MS based metabolic fingerprinting of apricot pistils after self-compatible and self-incompatible pollinations. (PubMed, Plant Mol Biol) - "Finally, polyketide-based macrolides similar to peloruside A and a hydroxy sphingosine derivative are suggested to be significant differential metabolites in the experiment. These results indicate a strategy of pollen tubes to protect microtubules and avoid growth arrest involved in sexual incompatibility reactions of apricot."

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A multiproducer microbiome generates chemical diversity in the marine sponge Mycale hentscheli. (PubMed, Proc Natl Acad Sci U S A) - "Other than supporting a scenario of cooperative symbiosis based on bacterial metabolites, the data provide a rationale for the chemical variability of M. hentscheli and could pave the way toward biotechnological peloruside production. Most bacterial lineages in the compositionally unusual sponge microbiome were not known to synthesize bioactive metabolites, supporting the concept that microbial dark matter harbors diverse producer taxa with as yet unrecognized drug discovery potential."

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Recent advances in microtubule-stabilizing agents. (PubMed, Eur J Med Chem) - "Microtubule-targeted drugs disrupt microtubule dynamics in distinct ways, and they are primarily classified into two groups: microtubule destabilizing agents (MDAs), such as vinblastine, colchicine, and combretastatin-A4, and microtubule stabilizing agents (MSAs), such as paclitaxel and epothilones. These MSAs mainly include paclitaxel, taccalonolides, epothilones, FR182877 (cyclostreptin), dictyostatin, discodermolide, eleutherobin and sarcodictyins, zampanolide, dactylolide, laulimalides, peloruside and ceratamines from natural sources, as well as small molecular microtubule stabilizers obtained via chemical synthesis. Then we discuss the application prospect and development of these anticancer compounds."

Journal • Review • Biosimilar • Oncology

Molecular modelling study on the differential microtubule-stabilizing effect in singly and doubly-bonded complexes with peloruside A and paclitaxel. (PubMed, Proteins) - "Our results revealed that the double association of PLA/TX (i) strengthens the lateral contact between tubulin dimers compared to singly-bonded complexes, (ii) favors a more parallel arrangement between tubulin dimers, and (iii) induces a larger restriction in the interdimeric conformational motion increasing the probability of finding structures consistent with 13-protofilaments arrangements. These results and are valuable to increase understanding about the molecular mechanism of action of MT-stabilizers, and could account for an overstabilization of MTs in doubly-bonded complexes compared to singly-bonded systems."

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Exploring the interaction of Peloruside-A with drug resistant αβII and αβIII tubulin isotypes in human ovarian carcinoma using a molecular modeling approach. (PubMed, J Biomol Struct Dyn) - "Peloruside-A (PLA) is a potent anti-mitotic agent showing excellent activity against taxol-resistant carcinoma. Furthermore, binding energy calculations showed that αβIIa has the highest binding towards PLA, whereas αβIIb and αβIII isotypes shows weaker associations with PLA. Our computational study provides valuable structural and energetic information to increase understanding into the origin of PLA resistance in human ovarian carcinoma and could be helpful to develop potential PLA analogs against specific β-tubulin isotypes expressed in cancer cells.Communicated by Ramaswamy H. Sarma."

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Metagenomic Exploration of the Marine Sponge Mycale hentscheli Uncovers Multiple Polyketide-Producing Bacterial Symbionts. (PubMed, mBio) - "We also identified an additional 188 biosynthetic gene clusters, including a pathway for biosynthesis of peloruside...We also find that the microbiome of M. hentscheli is stably maintained among individuals, even over long periods of time. Collectively, our data suggest a cooperative mode of defensive symbiosis in which multiple symbiotic bacterial species cooperatively contribute to the defensive chemical arsenal of the holobiont."

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Peloruside E (22-Norpeloruside A), a Pelorusane Macrolide from the New Zealand Marine Sponge Mycale hentscheli, Retains Microtubule-Stabilizing Properties. (PubMed, J Nat Prod) - "Peloruside E (5) is potently antiproliferative (HL-60, IC 90 nM, cf. 1, 19 nM) and polymerizes purified tubulin, albeit at a rate lower than that of 1."

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Modulation of lateral and longitudinal interdimeric interactions in microtubule models by Laulimalide and Peloruside A association. A molecular modeling approach on the mechanism of microtubule stabilizing agents. (PubMed, Chem Biol Drug Des) - "Besides structural effects, LAU/PLA induces a substantial strengthening of longitudinal interdimeric interactions, whereas lateral contacts are less affected by these ligands, as revealed by MM/GBSA and ASM calculations. These results are valuable to increase understanding about the molecular features involved in MT stabilization by LAU/PLA, and to design novel compounds capable of emulating the mode of action of these ligands."

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Peloruside A-Induced Cell Death in Hypoxia Is p53 Dependent in HCT116 Colorectal Cancer Cells. (PubMed, J Nat Prod) - "Knockout of the p21 gene had little effect on the activity of PLA in hypoxia. It was concluded that the response of cells to the microtubule-stabilizing agent PLA under hypoxic conditions is a p53-dependent process."

Journal • Preclinical

Function-Oriented Synthesis toward Peloruside A Analogues. (PubMed, Org Lett) - "The four-fragment strategy implemented features two aldol-type couplings with the central C12-C14 building block TES-diazoacetone and a late-stage ring-closing metathesis. Enantiopure analogue 18ab showed antiproliferative activity in the low micromolar range on NCI and MCF7 tumor cell lines."

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