Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models

Abstract

1. Ivermectin binds phosphorylation pocket of HSP27 to inhibit stress-mediated phopho-activation and depolymerization of HSP27
2. IVM also dose-dependently inhibited HSP27 interaction with unfolded insulin [suggested Video where Dr Ken Berry claims high insulin is a main driver to enlarged prostate symptoms.]
3. Ivermectin directly binds HSP27 and prevents its interaction with misfolded proteins
4. IVM inhibition of HSP27 is synergistically lethal to cells with oncogenic activation of EGFR or AR(androgen receptor)
5. Ivermectin inhibits phosphorylation and oligomerization of HSP27 in cancer cells.
6. IVM potently inhibited HSP27 phosphorylation in lung and prostate cancer as well as bladder and breast cancer cells.
7. The pharmacokinetic profile of IVM was determined to support tumor growth inhibition studies in vivo.
8. IVM significantly delayed docetaxel-resistant PC3 tumor progression
9. Repurposing IVM in cancer would require higher and longer dosing than its approved use as an antiparasitic.
10. While no significant adverse events were observed in the many in vivo experiments in this study, IVM activates GABA-A receptor activity, which can produce neurologic toxicity. To address these issues, IVM analogs have been designed with lower affinity to the GABA-A receptor while maintaining favorable oral bioavailability, pharmacokinetics, and HSP27 binding affinity, from which a lead compound will be selected for clinical development in combination with AR and EGFR/HER2 inhibitors.