Small Molecules To Inhibit PCSK9-LDLR

DESCRIPTION provided by applicant This proposal is to prepare small molecules that will inhibit the protein protein interaction between a protein called PCSK and the LDLR receptor This is an extremely well validated target for reduction of andquot badandquot cholesterol LDL and therefore controlling coronary artery disease Orally available small molecules are the preferred therapeutic modality for this target many companies have attempted to find ones that can inhibit PCSK LDLR receptor usually via high through out screening HTS yet no effective compounds have been reported to date Small Molecule PPI Mimics LLC andquot PPI Mimicsandquot owns intellectual property covering an innovative approach to designing small ligands that can perturb PPIs The core of this approach is a proprietary strategy called Exploring Key Orientations EKO that facilitates data mining of structurally characterized PPIs on a massive scale to identify patentable scaffolds to perturb a specific PPI or PPIs that can be perturbed by specific scaffolds PPI Mimics is generating revenue by identifying patentable chemotypes that can be used to target commercially valuable PPIs in collaboration with pharmaceutical partners and in the longer term plans to expand the scope of their income streams by preparing and testing patentable chemotypes that the company will develop internally In preliminary work an academic partner has i applied the EKO strategy to PCSK LDLR ii identified a chemotype to putatively inhibit this interaction and iii developed a general synthetic scheme for that scaffold This proposal seeks funds to make and test appropriate compounds in that chemotype series the ones made so far are model compounds and to publish this data to advertise the EKO technique and PPI Mimicsandapos interest in PCSK LDLR This will provide proof of principle that the EKO strategy can be used to identify compounds to inhibit PCSK LDLR Simultaneously PPI Mimics will use the EKO strategy to identify other chemotypes owned by the company that can be prepared and thoroughly evaluated in Phase PUBLIC HEALTH RELEVANCE The goal of this program is to identify small molecule leads for inhibiting PCSK LDLR PCSK inhibitors hold great promise for preventing cardiovascular disease through a new mode of action that is different to and potentially synergistic with the statins This work will help Small Molecule PPI Mimics grow by creating valuable IP for PCSK LDLR and demonstrating the overall value of our approach to developing PPI therapeutics PPIs in general are central to a new generation of pharmaceutical agents that will impact cancer neurological diseases heart conditions and many other major diseases