Ivermectin (IVM) also dose-dependently inhibited HSP27 interaction with unfolded insulin at Prostate Problems Forum

Abstract

HSP27 is highly expressed in, and supports oncogene addiction of, many cancers. HSP27 phosphorylation is a limiting step for activation of this protein and a target for inhibition, but its highly disordered structure challenges rational structure-guided drug discovery. We performed multistep biochemical, structural, and computational experiments to define a spherical 24-monomer complex composed of 12 HSP27 dimers with a phosphorylation pocket flanked by serine residues between their N-terminal domains. Ivermectin directly binds this pocket to inhibit MAPKAP2-mediated HSP27 phosphorylation and depolymerization, thereby blocking HSP27-regulated survival signaling and client-oncoprotein interactions. Ivermectin potentiated activity of anti–androgen receptor and anti-EGFR drugs in prostate and EGFR/HER2-driven tumor models, respectively, identifying a repurposing approach for cotargeting stress-adaptive responses to overcome resistance to inhibitors of oncogenic pathway signaling.

Keywords: Oncology

Keywords: Drug therapy

Notes from the study:

Ivermectin binds phosphorylation pocket of HSP27 to inhibit stress-mediated phopho-activation and depolymerization of HSP27
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.]
Ivermectin directly binds HSP27 and prevents its interaction with misfolded proteins
IVM inhibition of HSP27 is synergistically lethal to cells with oncogenic activation of EGFR or AR(androgen receptor)
Ivermectin inhibits phosphorylation and oligomerization of HSP27 in cancer cells.
IVM potently inhibited HSP27 phosphorylation in lung and prostate cancer as well as bladder and breast cancer cells.
The pharmacokinetic profile of IVM was determined to support tumor growth inhibition studies in vivo.
IVM significantly delayed docetaxel-resistant PC3 tumor progression
Repurposing IVM in cancer would require higher and longer dosing than its approved use as an antiparasitic.
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.

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

Abstract