Epigenetic proteins, such as histone methyltransferases represent important potential drug targets for indications like cancers, neurodegenerative disorders, and cardiovascular and metabolic diseases. At Reaction Biology Corporation (RBC), we are working toward the complete coverage of all epigenetic targets, including HMTs, to identify and improve epigenetic modulators that can be used in research and drug discovery. In this Phase II application, we have proposed three aims following successful Phase I studies to continue the understanding of HMTs' biological functions and as new drug targets.
The aims i nclude 1) Complete the screening of HMTs for identifying new probes and building the chemical-epigenetic data base; 2) Broader HTS and Structure-Activity Relationship (SAR) study to identify and increase the potency of NSD inhibitors; and 3) Evaluating NSD inhibitors' efficacy in cell based assays, and determining their kinetic MOAs and early DMPK/tox profiles. We'll meet the following milestones: (1) Develop and commercialize 10 or more HMT probes as general research tools for at least 5 HMTs; 2) Improve at least 2 lead compounds' potency into the nanomolar range against NSDs that have different structure scaffolds, with good cell based activity and DMPK profiles; and (3) we will be able to launch one of the largest publicly available chemical-epigenetic data bases built on the screening activities from the compound collections that include most of the FDA approved drugs, clinical trial agents, diversified libraries, and natural products.
Epigenetic proteins, such as histone methyltransferases represent important potential drug targets for indications like cancers, neurodegenerative disorders, and cardiovascular and metabolic diseases. If medicine is to move beyond conventional drug targets that represent symptomatic treatment only, then validation of these epigenetic enzymes and factors as drug targets remains a top priority for drug discovery. Chemical epigenetic inhibitors represent a powerful opportunity here. However, histone methylation is a relatively new discovery space, and the likely structures of HMT inhibitors are not well defined. Few small molecule inhibitors are available, either for laboratory research or fo lead development. Therefore, there is a significant and urgent need to develop assays and to identify new chemical probes for these targets. Small molecule probes would serve a valuable role in scientific investigations and serve as medicinal chemistry scaffolds for lead development and drug discovery. With the completion of this application we will be able to provide high quality probes that can be used 1) to validate epigenetic targets' biological activities, 2) as a standard reference to customers' drug development activities, and 3) as leads for potential therapeutic agents. In addition, we will be able to launch one of the largest publicly available chemical-epigenetic data bases built on the screening activities from the compound collections that include most of the FDA approved drugs, clinical trial agents, diversified libraries, and natural products.
