- Menin-MLL Inhibitors Reverse Oncogenic Activity of MLL Fusion Proteins in Leukemia
Translocations involving the mixed lineage leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) gene. Here we present what are, to our knowledge, the first small-molecule inhibitors of the menin-MLL fusion protein interaction that specifically bind menin with nanomolar affinities.These compounds effectively reverse MLL fusion protein-mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. (Grembecka et al Nat Chem Biol, 2012 http://www.ncbi.nlm.nih.gov/pubmed/22286128) See Research Highlight in Nature Reviews Drug Discovery http://www.nature.com/nrd/journal/v11/n3/full/nrd3689.html
- Therapy for CNS-Based Lysosomal Storage Diseases
In collaboration with Professors James Shayman and Richard Keep, the VMCC has contributed to the development of inhibitors of an enzyme that causes several rare but devastating lipid storage diseases, including Tay-Sachs and Gaucher. The ability to inhibit this enzyme in the central nervous system (CNS) is crucial for treatment of CNS-based lipid storage diseases but has eluded researchers, leaving no treatment options for affected patients.
We have recently shown that one of our compounds is able to reduce lipid levels in the brains of mice, suggesting that it penetrates into the CNS. We are planning to progress this compound into animal models of CNS-based lipid storage diseases.
Larsen et al. J Lipid Res, 2012
- Oral Antivirals for Neurotropic Arboviruses
Infections caused by insect-borne viruses (arboviruses) represent some of the most dramatic examples of disease re-emergence throughout the world. We recently reported the identification of a class of small molecules that inhibit RNA replication of the western equine encephalitis virus (WEEV), a neurotrophic alphavirus. The lead thienopyrrole compound 1 discovered via high throughput screening (HTS) in the University of Michigan Center for Chemical Genomics (CCG), possessed modest potency with low cytotoxicity.
In collaboration with Professors David Miller, David Irani, and Richard Keep, the VMCC has developed a novel series of indoles related to comound 1 that are more potent and more metabolically stable. One of these compounds was recently shown to improve survival in a mouse model of neuroadapted Sindbis virus infection.
Sindac et al. J Med Chem, 2012