The Doll research group is interested in anything that involves the synthesis and evaluation of interesting organic compounds. At the current time, our efforts are devoted mainly to drug discovery projects.
Drug Discovery Projects with Undergraduate Students
The Drew research group has devised a streamlined version of the preclinical drug discovery process used in the pharmaceutical industry. Using in vitro assays to evaluate the compounds we synthesize, the goal was to optimize the following:
- Drug potency
- Drug selectivity (to decrease toxicity)
- Drug like properties
- How well does the compound cross biological membranes including GI track and blood brain barrier membranes (BBB)?
- How well does the compound resist human metabolism using human liver microsomes?
By using the above process, they plan to identify improved compounds suitable for publication and/or progression into in vivo animal studies.
Current drug discovery projects
Oncology diseases: Develop compounds that reactivate mutant p53 in human tumor cells as a potential anti-cancer therapy.
The protein p53 is known as “The Guardian of the Genome”. It is the main gate keeper to control our cells if something goes wrong. Various stresses, including oncogenic mutations in the cell nucleus, will causes p53 to be activated by phosphorylation and acylation. This activated p53 enters the nucleus and functions as a transcription factor for many cell control proteins as shown in the Figure below. This includes cell growth arrest, apoptosis and the prevention of blood vessel growth. Cell growth arrest prevents the mutated cell from replicating and allows DNA repair mechanisms to take place. If the mutation cannot be repaired, p53 stimulates the synthesis of apoptotic proteins that kill the cell. If a tumor does develop, p53 will also activate the synthesis of anti-angiogenic agents that prevent new blood vessel growth which is necessary for a growing tumor.
In 50% of all human cancers, p53 is mutated and cannot perform its cell control functions. Poor prognosis is predicted in cancers with mutant p53. Since the p53 protein is a transcription factor for many proteins, it needs to have a flexible conformation. It seems that mutant p53 cannot achieve the necessary conformations to function properly. We and others have identified small organic molecules that can bind to mutant p53 and adjust the conformation to allow this mutant p53 to function as normal p53. That is, act as a transcription factor for cell control proteins. Currently, we have identified two structural classes that reactivate mutant p53 in human tumor cells. These compound classes are represented by the two structures, 1 and 2 shown below. We are in the process of synthesizing compounds in these classes so as to optimize the overall profile of the compounds.
- Vogelstein, D. Lane, A. Levine, Nature (2000), 408, 307.
- Brown, et al., Trends in Pharmacol. Sci. (2011), 32, 53.
- Dema, et al., J. Biol. Chem. (2010), 285, 10198
Central Nervous System (CNS) Diseases: Develop positive allosteric modulators of glutamic acid receptor 4 (mGluR4) for the treatment of CNS diseases such as Parkinson’s disease, Alzheimer’s disease and eating disorders.
The mGluR4 receptor is a cell surface G-protein receptor that controls ion channels. This is represented by the diagram shown below.
The strongest rationale for modulation of mGluR4 as a therapeutic is for Parkinson’s disease (PD). L-Dopa is the common drug treatment for PD. L-Dopa is metabolized to the neurotransmitter dopamine, which is lacking in PD patients. However, L-Dopa has serious systemic side effects, especially irreversible dyskinesia (uncontrolled muscle movements). Compounds that stimulate mGluR4 also seem to have beneficial effects on PD animal models. The dose of L-Dopa need to treat PD could be lowered by the co-administration of a mGluR4 activator, such that the dyskinesia side effect is diminished. We have been working with Lundbeck Research USA to develop such compounds. Currently, we have synthesized compounds in the cis-cyclohezyl-1,2-dicarboxamide class, and are evaluating their biological profile. Some of the compounds synthesized are shown below.
These compounds are synthesized as racemic mixtures, and then resolved with preparative chiral chromatography. These compounds will be analyzed for biological activity, as well as human metabolic rate and the ability to cross the blood brain barrier.
- K-E Bennouar, Neuropharmacology, (2013), 16, 160-169.