Inhibitors of microtubule polyglutamylation in mitosis for use as a medicament

PCT/EP2022/082269During mitosis, spindle microtubules (MTs) are polyglutamylated but the enzyme driving this post-translational modification and its functional implications in mitosis have not been elucidated. Here we indentify TTLL11 as an enzyme that catalyzes the polyglutamylation of the spindle MTs in mitosis. Using a combination of approaches in HeLa cells and zebrafish embryos we show that polyglutamylaation defines spindle MT dynamics preventing chromosome seregation error beyond the spindle assembly checkpoint. We also show that TTLL11 is consistently downregulated in human tumors, opening the exciting possibility that reduced spindle MT polygrulamylation could play an important role in aneuploidy, one of the mos salient features of cancer cells.The present invention refers to inhibitors of microtubule polyglutamylation in mitosis, preferably TTLL11 inhibitors, for use as a medicament, preferably in the treatment of diseases benefiting from the inhibition of microtubule polyglutamylation in mitosis, most preferably in the treatment of cancer.