SBIR-STTR Award

Multiple Myeloma (MM) is the second most common form of blood cancer and remains an incurable and deadly disease. Proteasome inhibitor (PI) therapy is a cornerstone in the treatment of MM, but resistance to this class of agent is an emerging challenge in the clinic. New therapeutic approaches that specifically target resistance are needed to maximize responses and ultimately produce cures. We have identified a hit-stage drug, compound E61, that selectively kills MM cells over normal cells, restores the activity of PIs in resistant MM cells, and cures more that 1/3 of mice with MM without any signs of toxicity. We have designed new derivatives of E61 that have optimized pharmaceutical properties. The specific goals of the proposed project are (1) to conclusively demonstrate increased metabolic stability and anti-MM activity of optimized E61 derivatives, and (2) to show superior in vivo activity of optimized derivatives using a mouse model of MM. Compounds will be tested as single agents and in combination with FDA-approved PIs. These study aims are based on strong preliminary medicinal chemistry work that identified structure activity relationships (SAR) of compound E61. This information has enabled the strategic design of the derivatives that we will test in the proposed study. The proposed experiments capitalize on industry standard assay systems for measuring pharmacological properties of new drugs in vitro, including metabolic stability in blood plasma and liver microsomes, and assays directly measuring drug metabolism by the catechol-O-methyltransferase (COMT) enzyme. In vitro assays for measuring anti-MM activity and predicting toxicity include the use of panels of genetically diverse PI sensitive and resistant MM cells and a variety of normal blood and fibroblast cell types. For evaluating the performance of novel derivatives in vivo we will use an established model of experimentally induced MM that accurately recapitulates the human MM pathology in NOD-SCID IL2Rgammanull (NSG) mice. Through the use of these tools, and predictions based on a breadth of preliminary data, it is our expectation that this work will deliver a promising new compound for the treatment of refractory MM.

Public Health Relevance Statement:
Narrative (Relevance) Proteasome inhibitors are cornerstone therapies in the treatment of Multiple Myeloma (MM). However, resistance limits their effectiveness and MM remains incurable today. Our project will develop a new class of drug that targets resistant MM and enhances the activity of proteasome inhibitors to improve the duration and quality of life for MM patients.

Project Terms:
26S proteasome; abstracting; Address; Animal Model; Animals; Aspirate substance; base; Bioavailable; biological adaptation to stress; Biological Assay; Biological Availability; Blood; bone; Bone Marrow; Bortezomib; cancer therapy; Catechol O-Methyltransferase; Cell Death; Cell Line; cell type; Cells; Chemicals; Clinic; Data; design; Development; Disease; Drug Compounding; drug metabolism; Drug Targeting; Effectiveness; Enzymes; esterase; Evaluation; Exhibits; expectation; FDA approved; Fibroblasts; Goals; Half-Life; Hematopoietic Neoplasms; Hepatic; Human; improved; In Vitro; in vitro Assay; in vivo; Industry Standard; Killings; Lead; Lesion; Liver Microsomes; man; Marketing; Measures; Metabolic; Modeling; Modification; Molecular; mouse model; multicatalytic endopeptidase complex; Multiple Myeloma; Mus; Normal Cell; Normal tissue morphology; novel; novel therapeutic intervention; novel therapeutics; oncology; Oxidation-Reduction; oxidative damage; Oxidative Stress; Pathology; Pathway interactions; Patients; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase I Clinical Trials; Plasma; Plasma Cells; Positioning Attribute; preclinical efficacy; preclinical safety; programs; Property; Proteasome Inhibitor; Quality of life; Refractory; research study; Resistance; response; restoration; Serum; Signal Transduction; small molecule; Staging; Structure; Structure-Activity Relationship; System; Tail; Testing; tool; Toxic effect; treatment response; Veins; Velcade; Vertebral column; Work

Multiple Myeloma (MM) is the second most common form of blood cancer and remains an incurable and deadly disease. Proteasome inhibitor (PI) therapy is a cornerstone in the treatment of MM, but resistance to this class of agent is an emerging challenge in the clinic. New therapeutic approaches that specifically target resistance are needed to maximize responses and ultimately produce cures. We originally identified hit-stage compound, E61, that selectively killed MM cells over normal cells, restored the activity of PIs in resistant MM cells, and showed early signs of anti-MM activity in a mouse model without any signs of toxicity. In the Phase 1 component of the project we engaged in a medicinal chemistry program that delivered a significantly more potent lead molecule, E64FC26, with improved drug-like properties, robust in vivo efficacy, and a strong patent position. Furthermore, Phase 1 identified protein disulfide isomerase (PDI) as the molecular target of this new class of small molecule. PDI regulates protein folding and is therefore a rational drug target for MM, which is a cancer that produce mass amounts of protein and is highly sensitive to disruption in protein homeostasis. Despite this rationale, no PDI inhibitors have advanced to clinical trials in humans, primarily due to limitations in the in vitro PDI assays that are used in drug discovery. The specific goals of the Phase 2 project are (1) to complete the chemical optimization of E64FC26 to further improve its pharmaceutical properties and enhance oral bioavailability, (2) to demonstrate the anti-MM efficacy of optimized E64FC26 in multiple mouse models of MM, and (3) to conduct dose range finding/maximum tolerated dose determining studies along with toxicokinetics in rats. These study aims are based on strong preliminary data and a large-scale medicinal chemistry program that identified key structure activity relationships (SAR) and a potent PDI inhibitor. This information has enabled the strategic design of a short-list of derivatives that we will test in the proposed study. Industry standard ADME assays and pharmacokinetics will be used to evaluate new E64FC26 derivative, and established mouse models of MM that recapitulate the human pathology and predict clinical efficacy will be used. Industry standard dose range finding studies will facilitate formal GLP-compliant toxicology that will enable an IND application to the FDA. Through the use of these tools, and predictions based on a breadth of preliminary data, it is our expectation that this work will deliver a promising new drug candidate for the treatment of refractory MM.