Timothy L. Macdonald, PhD
Synthetic organic and bioorganic medicinal chemistry
The over-arching goal of the Lynch Lab's research is to understand better the biology of lysophospholipid signaling, particularly in the context of pathologies. The central strategy remains the development of tools (mostly small molecules) with which to probe lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) biology; in the past year they have complemented this chemical biology approach with mouse genetics. The chemical entities that were developed during the past two years include a high affinity LPA3 receptor selective antagonist, S1P1 receptor selective agonists, S1P1 receptor selective agonists that are pro-drugs and a S1P1/S1P3 receptor antagonist. The synthesis of all of these molecules was done in the laboratory of their long-term collaborator, Professor Timothy L. Macdonald.
The LPA3 receptor selective agents have been crucial in identifying that receptor type as functioning in the LPA-mediated kidney damage in a mouse model of acute renal failure, as documented by another collaborator, Professor Mark D. Okusa. The S1P receptor reagents have been helpful in understanding the mechanism of action of the immunosuppressant drug, FTY720, and were instrumental in identifying the endothelial S1P receptor type (S1P1) responsible for monocyte adhesion to the vascular wall, which is an early step in the atherosclerotic process. Both LPA and S1P receptor antagonists are being tested currently as anti-angiogenesis agents in the chicken CAM assay and selected compounds will be taken forward to matrigel implant assays in rodents. Very recently, the Macdonald Lab has provided them with a high affinity LPA1 receptor antagonist that they believe will be stable metabolically; this compound will be tested by Professors Theresa Guise and John Chirgwin in a breast cancer (MDA MB231 cells) model of bone metastasis - a phenotype that is accelerated by overexpression of the LPA1 receptor in these cells. The lab is exploring also the use of a secreted, LPA-generating, non-mammalian (brown recluse spider) phospholipase D to learn the effects of local LPA production on tumor development in athymic mice.
Genetic tools include a conditional KO of the LPA3 receptor gene (contracted, delivery Fall 2005), LPA1 receptor KO mice (gift) and a sphingosine kinase 2 (SPHK2) KO mouse (internal). The SPHK2 null mouse allowed us to document that the pro-drug, FTY720, is metabolized to the active principal (FTY720-P), by this isotype. This discovery is described in a manuscript submitted for publication recently; Professors Vic Engelhard, Ken Tung, Tim Macdonald and Klaus Ley are co-authors.