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- Cummings, M
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Upon completion of his B.S. studies (1979) in chemistry at the University of Athens, Greece, Michael Malamas attended graduate studies at the University of Pennsylvania, in Philadelphia, where he received a Ph.D. in organic chemistry in 1983. His Ph.D. work was focused on the synthesis of natural products (jatrophone derivatives, bertyadionol) with anti-tumor properties. Afterwards, he pursued post-doctoral studies at the Massachusetts Institute of Technology, where he studied the synthesis of natural products (bryostatins) with anti-tumor properties.
In 1985, he joined Wyeth in Princeton and during the last 20 years he has been involved in several therapeutic areas studying diabetes, obesity, inflammation, and Alzheimer’s Disease.
Soon after his employment at Wyeth, he developed a great interest in the fundamental protein-ligand interactions and collaborated with the Structural Biology Group and learned several modeling systems to expedite the design and discovery of new biologically active molecules.
He has successfully applied the structure-based drug design approach in several of his research projects, such as diabetes (inhibitors of protein tyrosine phosphatase 1B), obesity (beta3-adrenergic agonists), inflammation (estrogen receptor-beta agonists), and Alzheimer’s Disease (small molecules as inhibitors of beta-secretase).
The main thrust of the structure-based work includes the X-ray analysis of numerous complexes of ligands with the targeted proteins, which together with modeling studies explain the biological findings and set forth new strategies to rapidly address key structure-activity relationship issues. He has collaborated with members of the Computer-Aided Molecular design group in virtual screens of protein targets such as beta-secretase and estrogen receptor-beta.
He has published over 100 scientific papers and patents during this period.
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Structure-Based Design of Estrogen Receptor-beta Selective Compounds
Michael S. Malamas, Wyeth
Michael S. Malamas, Heather A. Harris, James C. Keith, Jr., Robert McDevitt, Iwan Gunawan, Christopher P. Miller, Eric Manas and Richard Mewshaw
The discovery of a second subtype of the estrogen receptor (ER-beta) in 1996 prompted an intense discovery effort within the scientific community to identify ER-beta selective ligands in order to elucidate the receptor’s physiological role in mediating estrogen action. However, until very recently ER-beta’s physiological role has remained unclear. One approach that has not yet been fully exploited to date is the use of highly ER-beta selective ligands to elucidate the functional role of ER-beta. Toward this end, we have designed highly potent and selective agonists for ER-beta and have characterized their activity in several clinically relevant rodent models.
While only two subtle amino acids differences are present in the ligand binding domains of the two ER-alpha?and ER-beta isoforms, our structure-based approach enabled us to rapidly advance our initial leads to successful candidates. X-ray crystallography data and molecular modeling tools allowed us to exploit a single amino acid difference between the two ERs (ER-betaIle421 to ER-alphaMet373). Several ligands were found to highly bind to ER-beta with IC50 values of 3-5 nM, which are similar to 17beta-estradiol. However, unlike estradiol, these ligands are >100 fold selective for ER-beta over ER-alpha.
Our ER-beta selective ligands exhibited little or no utility in hormone therapy or as contraceptive agents (e.g., uterotrophy, osteopenia, mammotrophy, thermoregulatory dysfunction, and ovulation) where nonselective estrogens (e.g. 17beta-estradiol) or ER-alpha selective agonists are known to have robust effects. However, we have found that ER-beta selective agonists have a dramatic beneficial effect in animal models of various chronic inflammatory conditions (inflammatory bowel disease, arthritis) and they are currently undergoing clinical trials as novel therapies to treat such conditions. The data suggest that one function of ER-beta may be to modulate the immune response, and that ER-beta selective agonists may offer a novel therapy to treat chronic inflammatory conditions.
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