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Centrosomes are major microtubule organizing centers in mammalian cells, which play a pivotal role in mitosis. Centrosome amplification is a hallmark of human cancers that can trigger cancer cell invasion. To survive, cancer cells cluster extra centrosomes to achieve pseudo-bipolar division. The invention aims to prevent clustering of extra centrosomes by prematurely activating centrosomes to induce microtubule nucleation before mitotic onset.
Keywords: centrosome, human cancer, microtubule nucleation, CPAP-tubulin Inhibitors, drug resistant cancer
Tubulin, by interacting with the centrosomal Protein CPAP, negatively regulates CPAP-dependent peri-centriolar material recruitment and concurrently microtubule nucleation. Screening for compounds that perturb CPAP-tubulin interaction led to the identification of novel compounds, which selectively bind at the CPAP binding site of tubulin. These compounds prematurely activate extra centrosomes to nucleate microtubules causing cancer cells to undergo centrosome declustering, multipolar mitosis, prolonged mitotic arrest and cell death. 3D-organotypic invasive assays reveal those compounds to have broad anti-invasive activity against various cancers including tyrosine-kinase inhibitor (TKI)-resistant EGFR- and KRAS-mutant non-small cell lung cancers. Moreover, those compounds have been shown to impair in vivo growth of xenograft tumors in nude mice. Therefore, cancer cells are vulnerable to extra centrosomal activation, which may serve as a novel general approach to target various cancers including drug resistant cancers.
Novel compounds are offered for licensing.
- Novel target in cancer therapy
- First-in-class compounds
- Therapy option of drug resistant cancers
A PCT-application is pending.
Mariappan, A., et al. (2017) Premature activation of extra centrosomes by a CPAP-tubulin inhibitor selectively prevents cancer cellular proliferation (under review in Nature Chemical Biology)
Zheng, X., et al. (2016) Molecular basis for CPAP-tubulin interaction in controlling centriolar and ciliary length. Nat Commun.7: 11874.
Gabriel, E., et al. (2016) CPAP promotes timely cilium disassembly to maintain neural progenitor pool. EMBO J. 35: 803-19