Research
Featured Publications
Chacko et al, Expanding benzoxazole based inosine 5’-monophosphate dehydrogenase (IMPDH) inhibitor structure-activity as potential anti-tuberculosis agents. J. Med. Chem. 61, 4739-4756 (2018). abstract
Mandapati et al, Repurposing Cryptosporidium Inosine 5’-monophosphate Dehydrogenase Inhibitors as Potential Antibacterial Agents. ACS Med. Chem. Lett, 5, 846-850 (2014). ACS Editors Choice. abstract
IMPDH-targeted antimicrobial drug discovery
Microbial infections are now the second leading cause of death worldwide. Many commonly used antibiotics have been rendered ineffective by the upsurge of drug resistance, and years of neglect have left a mere trickle of new antibiotics in the pipeline. New targets, and new drugs, are urgently needed. Although IMPDH inhibitors are used in immunosuppressive, cancer and antiviral therapy, as yet IMPDH inhibitors have not been exploited in antimicrobial applications because no bacterial-selective IMPDH inhibitors have been identified. We have been identified low nanomolar inhibitors of bacterial IMPDHs with >250 selectivity versus the human enzyme. These compounds display potent antibacterial activity against Mycobacterium tuberculosis and Staphylococcus aureus, two of the most serious threats. While the antibacterial activity of many of these compounds clearly derives from inhibition of IMPDH, other compounds also engage an additional target(s). Multi-target antibiotics have a greatly diminished risk of developing resistance than single target compounds, so the observation that the pharmacophore of IMPDH inhibition overlaps with that of another essential process is exciting. We are currently optimizing IMPDH inhibitors as well as identifying the unknown target(s) to provide a foundation for multi-target antibiotic development. The research team includes Greg Cuny (UHouston), Helena Boshoff (NIH), Andrzej Joachimiak (Argonne) and Joanna Goldberg (Emory).
Targeted protein degradation
Targeted protein degradation is an emerging strategy in drug discovery. Drugs that induce the degradation of their target have several potential advantages over traditional agonists/antagonists: (1) New protein targets must be synthesized to reverse the effect of the drug, potentially extending the duration of the drug’s effect; (2) All the domains of the protein target are inactivated, potentially inducing different effects; (3) Only catalytic amounts are required for efficacy, lowering dose and (4) Simple binders can be converted into functional compounds, which may address targets previously considered “undruggable”. A single over-arching strategy has been utilized in the rational design of drugs inducing target degradation: localization of the target protein to a ubiquitin E3 ligase with chimeric molecules consisting of a target recognition ligand linked to an E3 ligase binding ligand. These molecules induce formation of a target•drug•E3 ligase ternary complex, resulting in ubiquitination and ultimate degradation of the target protein via the 26S proteasome. We have pioneered an alternate strategy where the recognition ligand is tethered to a moiety that binds to the 20S proteasome, inducing degradation while bypassing ubiquitination. We are now further developing this methodology. We expect that this work will also yield important new insights into the pathways of protein quality control.
Featured Publications
Shi et al, Boc3Arg-linked ligands induce degradation by localizing target proteins to the 20S proteasome. ACS Chemical Biology 11, 3328-3337 (2016). PMC5524191
Long et al. Inhibitor Mediated Protein Degradation. Chemistry & Biology 19, 629-37 (2012). Nature News & Views, abstract
A novel inhibitor of mTOR complex 1
Cancer and neurodegeneration are arguably the most prevalent and devastating diseases associated with aging. Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) signaling pathways is common feature of these diseases, as well as for neurological diseases such as epilepsy and autism spectrum disorders. mTORC1 inhibition is a promising treatment strategy for these diseases. mTORC1 inhibitors also increase lifespan and improve learning and memory in mice.
mTORC1 is a master regulator of cell growth and a complex network of growth factor signaling and nutrient sensing pathways regulate mTORC1 activity. We have discovered a small molecule (CB3A) that inhibits mTORC1 signaling via a novel mechanism. CB3A is a more effective, if less potent, inhibitor of translation than the eponymous mTORC1 inhibitor rapamycin. Thus CB3A-inspired drugs may provide a therapeutic benefit for some diseases. However, mTORC1 hyperactivation can derive from diverse underlying molecular mechanisms. We are delineating the mechanism of CB3A action in order to identify which diseases are most likely to respond to a CB3A-based treatment strategy. Understanding the mechanism of CB3A inhibition is also likely to identify new potential targets as well as new facets of mTORC1 regulation.
Featured Publication
Coffey et al, Ubiquilin Mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling. J. Biol. Chem. 291, 5221-33 (2016). PMC4777855
