Overcoming the challenges of Human HSP60 and ERK5 inhibition in cancer through heterobifunctional degraders and improved analogs
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Authors
Wilson, Mark
Clate, Nicholas
Trosch, Liam
Montague, Charlotte
Satin, Gary
Issue Date
2023-04-28
Type
Other
Language
en_US
Keywords
Scholarship Sewanee 2023 , University of the South , ERK5 , Cancer , HSP60 , MAPK7 , Heterobifunctional Degraders , PROTAC , AUTAC , VL-285 , FBnG
Alternative Title
Abstract
Human Heat Shock Protein 60kDa (HSP60) and Human Extracellular Regulated Kinase 5 (ERK5) are two distinctly functional proteins that are present in a variety of cancers. Because of this, both proteins have become of recent interest for development of anti-cancer therapeutics. Previous small molecule Inhibitors (SMI) have been developed for HSP 60 that target ATP hydrolysis sites (Type 1 inhibitors) or target important structural Cysteine residues of the protein (Type 2 inhibitors). Both have seen limited success of anti-cancer activity in vivo, but are limited by both required concentration and unwanted side effects. Our approach to this problem is taking pre-existing SMIs and creating heterobifunctional degraders, known as Proteolysis targeting Chimeras (PROTAC), using polyethylene glycol (PEG) linkers and E3 ligase ligands. This allows for manipulation of the ubiquitin Proteasome System (UPS) to degrade target proteins . Two of the designed HSP60 inhibitors use this methodology (using mizoribine and epolactaene tert-butyl ester as HSP60 ligands), while our third is an improved analog of myrtucommulone that aims to reduce its off target reactions with the microsomal prostaglandin E2 synthase 1 (mPGES-1) and 5-lipoxygenase (5-LOX) enzymes, involved in the arachidonic acid synthesis pathway. ERK5 is a signaling kinase found in the relatively new fourth Mitogen-activated Protein (MAP) Kinase pathway. Typical inhibition by SMIs has caused paradoxical activation of the protein rendering this approach null. Furthermore, PROTAC design using multiple ERK5 ligands has been shown to have no anticancer activity. Because of this, our approach to ERK5 is designing other heterobifunctional molecules using a different methodology. We use BIX 02189 as our ERK5 ligand, a PEG linker, and FBnG as an S-guanylation impersonator molecule. This methodology hijacks the macroautophagy system instead of the UPS. These molecule designs are a good starting point for the future of ERK5 and HSP60 targeted therapeutics.
Description
Citation
Publisher
University of the South