Small Molecule Inhibitors of the Tubulin Carboxy-Peptidase AGBL2
Categories: “Cancer Therapeutics“
Reference #: 2010-044
This invention relates to chemical inhibitors of AGBL2, which has recently been identified as the carboxy-peptidase responsible for α-tubulin detyrosination. Elevated levels of detyrosinated α-tubulin are found in microtubules of neurons and poor prognosis cancers. Microtubules rich in detyrosinated α-tubulin are more stable than their tyrosinated counterparts and enhanced stability of microtubules is thought to promote chemotherapeutic resistance, epithelial to mesenchymal transition and cell motility, all of which contribute to cancer progression. Chemical inhibition of AGBL2 would reduce the stability of cancer cell microtubules, thereby making tumor cells less motile and more susceptible to microtubule-targeted therapeutics.
Potential therapeutic for the treatment of multiple cancers as well as neurological diseases
- Detyrosinated tubulin is enriched in tumor cells allowing for interventions specifically in cancer cells
- Inhibition of tubulin detyrosination may enhance the efficacy of traditional microtubule-targeted therapies such as vincristine and taxol.
Stage of Development
Lead compounds have been designed, synthesized and tested for efficacy in vitro.
“Tumor suppressor RARRES1 interacts with cytoplasmic carboxypeptidase AGBL2 to regulate the α-tubulin tyrosination cycle”. Sahab ZJ et. al., Cancer Research 2011 Feb 15; 71(4):1219-28
Patent application filed.