Numerate seeks to partner its programs for development in order to focus on its advantage in lead design and optimization.
Dysfunction of FFA1 and FFA4 has been associated with obesity and diabetes; accordingly, they are important emerging targets for the treatment of Type 2 diabetes, obesity and related co-morbidities. Our goal in this program is to identify and advance selective FFA4 agonists and dual-acting FFA1+FFA4 agonists as potential first-in-class therapies.
FFA1 and FFA4 are G-protein coupled receptors, integral membrane proteins that are difficult to address through structure-based drug design. Furthermore, FFA4 signals through both G-protein and beta-arrestin pathways, adding further complexity to the design process. However, Numerate’s ligand-based approach allows us to build accurate predictive models for functional effects (FFA1 agonism, FFA4GP agonism, FFA4betaA agonism), which we have used to design diverse and novel agonists that meet each of our profiles.
In cardiovascular disease, we are designing modulators of the ryanodine receptor 2 (RyR2) for the treatment of heart failure and atrial fibrillation. RyR2 is the calcium-induced calcium release channel that, in cardiomyocytes, mediates excitation-contraction coupling via release of calcium from stores within the sarcoplasmic reticulum. Mutation or non-genetic modification of RyR2 can lead to defects in calcium handling that underlie arrhythmia and heart failure. Ryanodine receptor dysfunction has also been associated with muscle weakness in muscular dystrophy and with cell death in neurodegenerative disorders. Our goal in this program is to identify and advance multiple novel series of ryanodine receptor modulators as potential first-in-class therapies.
Ryanodine receptors are very large integral membrane proteins that possess multiple distinct binding sites for small molecule modulators and associate with many other proteins. Little high-resolution structural information is available for ryanodine receptors, and robust high-throughput assays for ryanodine receptor function have not been reported. These characteristics have made ryanodine receptors difficult to address using traditional drug discovery tools and strategies. However, Numerate’s approach is not subject to these limitations and has allowed us to successfully initiate our program with only a small amount of input data.
In Alzheimer’s disease (AD), we are designing small molecule ligands for apolipoprotein E4 (apoE4). ApoE4 is the major genetic risk factor for AD, with 65-80% of AD patients carrying an apoE4 allele, and apoE4 has been shown to play a fundamental mechanistic role in AD pathogenesis. In contrast to other apolipoprotein isoforms, apoE4 prefers a compact, globular structure. This structure renders apoE4 susceptible to proteolysis, which in turn releases fragments that cause cytoskeletal and mitochondrial dysfunction leading to neurotoxicity. Toxic apoE4 fragments are greatly elevated in the cerebrospinal fluid and brains of AD patients.
Merely blocking apoE4 synthesis is not a viable therapeutic approach, since apoE4 is the major transporter of cholesterol in the brain and is essential for neuronal maintenance and repair. An alternative strategy, which we are pursuing in collaboration with Dr. Robert Mahley of the J. David Gladstone Institutes and with support from the Wellcome Trust, is to use small molecules to associate with and disrupt the compact structure of apoE4 that is ultimately responsible for its toxicity. Such apoE4 structure correctors (apoE4SCs) represent a therapeutic approach that is distinct from any previous AD program.