Objective: Hippo signaling pathway is known to regulate organ development. In Hippo signaling pathway, YAP or TAZ works as a transcriptional co-activator and forms a transcriptional complex with TEAD. In several cancers, upstream factors in Hippo pathway are inactivated by genetic alterations. When the upstream factors are inactivated, TEAD is activated and forms a complex with YAP/TAZ resulting in enhancement of cell proliferation, drug resistance and so on. In the activation process, S-palmitoylation of TEAD is necessary for binding to YAP/TAZ. Malignant pleural mesothelioma (MPM) is one of cancer types which have genetic alterations in Hippo pathway genes. Although YAP/TAZ-TEAD inhibitor should be an ideal drug for MPM therapy, there are only a few reports about YAP/TAZ-TEAD inhibitor and the efficacy and selectivity are not sufficient. In this study, we succeeded to synthesize a small molecule TEAD inhibitor, K-975, and evaluated its mechanism of action and anti-tumor effect against MPM. Materials/methods: Inhibitory activity of K-975 on YAP/TAZ-TEAD protein-protein interaction (PPI) was evaluated in surface plasmon resonance (SPR) and co-immunoprecipitation assay. The effect of K-975 on palmitoylation status of TEAD was also evaluated. The three-dimensional structure of YAP-binding domain of TEAD1 in complex with K-975 was determined by X-ray crystallography. Anti-tumor effect of K-975 was evaluated by using MPM cell lines. Furthermore, using a derivative of K-975, 2 week-toxicity studies in rats and monkeys were performed. Results: K-975 inhibited YAP-TEAD and TAZ-TEAD PPI in NCI-H226 cells, a human MPM cell line. Also, K-975 inhibited palmitoylation of TEAD. The crystal structure revealed that K-975 directly bound to cysteine residue in YAP-binding domain of TEAD1. This cysteine residue is highly conserved in TEAD family and known as a site of S-palmitoylation. K-975 inhibited the cell proliferation of NCI-H226 with GI50 of about 20 nmol/L. K-975 also induced a change of gene expressions similar to that induced by YAP knockdown. In vivo experiments, K-975 strongly suppressed the tumor growth in several s.c. xenograft models and showed a significant survival benefit in an orthotopic xenograft model. However, 2 week-toxicity studies of a K-975 derivative with optimized bioavailability showed some pathological findings which suggested the renal toxicity. Conclusion: We synthesized a first-in-class drug which directly binds to TEAD protein and inhibits YAP/TAZ-TEAD PPI. K-975 showed a strong anti-tumor effect in pre-clinical MPM models. Although the renal toxicity might cause some difficulty in clinical use, we believe that a K-975 derivative has a possibility to become an effective drug candidate for MPM therapy. Citation Format: Ayumi Kaneda, Toshihiro Seike, Takeshi Uemori, Kensuke Myojo, Kensuke Aida, Tomohiro Danjo, Takahiro Nakajima, Daisuke Yamaguchi, Tomoko Hamada, Yoshiro Tsuji, Kaori Hamaguchi, Mai Yasunaga, Nobumasa Otsubo, Hideyuki Onodera, Yoichi Nishiya, Michihiko Suzuki, Junichi Saito, Toshihiko Ishii, Ryuichiro Nakai. Discovery of a first-in-class TEAD inhibitor which directly inhibits YAP/TAZ-TEAD protein-protein interaction and shows a potent anti-tumor effect in malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3086.
Alkaliphilic Bacillus sp. strain 41M-1, isolated from soil, produced xylan-degrading enzymes extracellularly. Optimum pH for the crude xylanase preparation was about pH 9, confirming the production of novel alkaline xylanase(s) by the isolate. Xylanases were induced by xylan, but were not produced in the presence of xylose, arabinose or glucose. Xylanase productivity was influenced by culture pH, and production at pH 10.5 was higher than that at pH 8.0. Zymogram analysis of the culture supernatant showed the alkaline xylanase with a molecular mass of 36 kDa.
The aim of this study was to investigate the mechanism of inhibition of Eg5 (kinesin spindle protein), a mitotic kinesin that plays an essential role in establishing mitotic spindle bipolarity, by the novel small molecule inhibitor K858. K858 was selected in a phenotype-based forward chemical genetics screen as an antimitotic agent, and subsequently characterized as an inhibitor of Eg5. K858 blocked centrosome separation, activated the spindle checkpoint, and induced mitotic arrest in cells accompanied by the formation of monopolar spindles. Long-term continuous treatment of cancer cells with K858 resulted in antiproliferative effects through the induction of mitotic cell death, and polyploidization followed by senescence. In contrast, treatment of nontransformed cells with K858 resulted in mitotic slippage without cell death, and cell cycle arrest in G 1 phase in a tetraploid state. In contrast to paclitaxel, K858 did not induce the formation of micronuclei in either cancer or nontransformed cells, suggesting that K858 has minimal effects on abnormalities in the number and structure of chromosomes. K858 exhibited potent antitumor activity in xenograft models of cancer, and induced the accumulation of mitotic cells with monopolar spindles in tumor tissues. Importantly, K858, unlike antimicrotubule agents, had no effect on microtubule polymerization in cell-free and cellbased assays, and was not neurotoxic in a motor coordination test in mice. Taken together, the Eg5 inhibitor K858 represents an important compound for further investigation as a novel anticancer therapeutic. [Cancer Res 2009;69(9):3901-9]
[structure: see text] Eight new compounds, MPC1001 and MPC1001B-H, were isolated from the fungus Cladorrhinum sp. KY4922. Multiple NMR experiments and CD data revealed MPC1001 to be an O-methyl derivative of emestrin, a 15-membered antifungal antibiotic containing a unique epidithiodioxopiperazine skeleton. Other compounds were elucidated to be structurally related novel analogues. MPC1001 and the analogues exerted potent antiproliferative activities against a human tumor cell line.
[structure: see text] UCS1025A and B, novel pentacyclic polyketides with an unprecedented furopyrrolizidine skeleton, were isolated from the fungus Acremonium sp. KY4917. The structures and stereochemistry were elucidated by a combination of two-dimensional NMR and X-ray crystallographic analysis. UCS1025A showed unique chemical equilibria involving three tautomeric isomers and exhibited antimicrobial activity and antiproliferative activity against human tumor cell lines.
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