Combinatorial Molecules For Tuberous Sclerosis

David J. Austin, Ph.D.
Department of Chemistry
Yale University, New Haven, CT

TSC Research Effort

The Austin research laboratory is focused on a research effort that is designed to test the hypothesis that low molecular weight chemical inhibitors of cellular function can be created to inhibit biological targets relevant to Tuberous Sclerosis, through the use of combinatorial and computational chemistry to generate biased libraries.

Our laboratory has extensive experience in combinatorial chemistry and has developed a number of novel chemical scaffolds that will be used as probes in collaboration with other Tsc researchers, such as Tian Xu of the Yale University Medical School, to test these compounds against known Tsc therapeutic targets.

Small Molecule Kinase Inhibitors

In collaboration with the Deisseroth lab of the Sidney Kimmel Cancer Center, our group has recently identified a family of small molecules that appear to inhibit the in vitro P210bcrabl kinase proliferation of a myeloid cell line (32DP210bcrabl) in the high to mid nM (100-500 nM) range. On the basis of competition studies, one of these structures in competitive and additive with STI-571 and therefore appears to inhibit the P210bcrabl kinase by interacting with the same site as STI-571. In addition, a second structure has been identified which acts synergistically with STI-571, resulting in dramatic inhibition of the P210bcrabl dependent in vitro proliferation of the P210bcrabl cell line in the 10 nM concentration range. These studies suggest that the inhibitory effect of the drug on the P210bcrabl dependent in vitro proliferation is due to the interaction of the drug with P210bcrabl at a site on the kinase oncoprotein which is distinct from that with which STI-571 interacts. It is also possible that the drug may act on some downstream or parallel pathway that affects P210bcrabl dependent proliferation within the cell. The important prediction of this work is that this second compound may be non cross resistant with STI-571, i.e., this drug may be inhibitory for CML cells in which resistance to STI-571 has developed. This opens up the possibility that in the very near future, it may be possible to develop combination drug therapy of CML thereby inducing remissions which will be much more durable in a much greater percentage of CML patients than currently possible with STI-571.

Relevance to TSC

Kinases are prolific cellular proteins and have been implicated in many disease states, including Tsc related disorders. Since our approach to developing therapeutics is based on molecular scaffolds, a single series of molecules serve as the starting point for new therapies in many diseases. We plan to use a number of libraries that were previously constructed in our laboratory as a starting point for developing a novel chemical therapy for Tsc.

Several cell lines related to Tsc are currently under investigation in the Tian Xu laboratory at the Yale medical School. The Xu lab will evaluate these molecular libraries for activity and forward the identity of active molecules back to our lab. At this point a second, modified and library of molecules will be created to focused and improve the activity of the first set. This second set will then be evaluated for efficacy and the cycle will continue until a single molecule is selected as the most potent library member.

This optimized molecule can then be evaluated for efficacy in animal studies and continue as a potential drug therapy. The benefit of this feedback-loop approach to drug design is that it can be performed for each Tsc disorder for which there is a cellular phenotype, each assay leading to s different potential drug.

Related Austin Group Publications

"The Diastereofacial Solid Phase Synthesis and Self-Promoted Cleavage of a [2.2.1] Bicyclic Diversity Scaffold" Savinov, S. N.; Austin, D. J. Org. Lett., 2002, Submitted.

"Modular Evolution of a Chiral Auxiliary for the 1,3-Dipolar Cycloaddition of Isonchnones with Vinyl Ethers" Savinov, S. N.; Austin, D. J. Org. Lett., 2002, Submitted.

"Using Adenosine-Anchored Diversity Probes to Explore the Chirality of the ATP Site: Distinguishing Between HER-2 and HER-4 Tyrosine Protein Kinases" Liu, F.; Johnson, E. F.; Austin, D. J.; Anderson, K. F. J. Am. Chem. Soc., 2002, Submitted.

"A General Synthesis of 5'-Azido-5'-Deoxy-2'3'-O-Isopropylidene Nucleosides" Liu, F.; Austin, D. J. J. Org. Chem., 2002, In Press.

"An Improved Synthesis of (4S)-4,5-O-Isopropylidenepent-(2Z)-Enoate" Koenig, S. G.; we, R. S.; Austin, D. J. Synth. Comm. 2002, 32, In press.

"The Cloning of Human Genes Using cDNA Phage Display and Small-Molecule Chemical Probes" Savinov, S. N.; Austin, D. J. Comb. Chem. High Throughput Screen 2001, 4, 593-7.

"Synthesis of a New Class of 5'-Functionalized Adenosines Using a Rh(II) Catalyzed 1,3-Dipolar Cycloaddition" Liu, F.; Austin, D. J. Org. Lett., 2001, 3, 2273-76.

"Synthesis of 5'-Functionalized Adenosine: Suppression of Cyclonucleoside Formation " Liu, F.; Austin, D. J. Tetrahedron Lett. 2001, 42, 3153-4.

"Combinatorial Chemistry in Cancer Drug Development" Leonard, K. A.; Deisseroth, A.; Austin, D. J. The Cancer Journal 2001, 7, 79-83.

"Molecular Therapy of Cancer" Deisseroth, A.; Pysrri, A.; Austin, D. J. in The Principles and Practice of Oncology, 6th Ed., DeVita, V. T.; Hellman, S. and Rosenberg, S. A., Eds., Lippincott Williams & Wilkins, Philadelphia, 2000, p 3180-3189.

"Combinatorial Chemistry" Austin, D. J. in The Principles and Practice of Oncology, 6th Ed., DeVita, V. T.; Hellman, S. and Rosenberg, S. A., Eds., Lippincott Williams & Wilkins, Philadelphia, 2000, p 356-362.

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