Non-melanoma skin cancers (NMSCs) are the most common skin malignancy and in organ transplant patients the incidence of these cancers increase by 10 to 250 fold. The NMSCs in transplant recipients are more aggressive in behavior. Therefore, prevention of NMSC in transplant patients is a high priority. While retinoids are generally effective in prevention of NMSC, these agents are associated with severe lipid toxicities thus precluding them from chronic administration. The overall objective of the program project is to identify a potent and safe rexinoid and translate it into clinical use for prevention of NMSCs. Towards achieving this goal, Core 2 will synthesize rexinoids to support the aims of Project 2, Project 3 and Core 3. Our laboratory has developed two separate structural classes of rexinoids, which are highly effective in preventing cancers without increasing the lipid levels. One example of these new rexinoids is UAB30, which is also being tested against NMSC and is effective in preclinical models at preventing NMSC without increasing the lipid levels. In addition to UAB30, a second structural class of retinoids is being developed which are also effective in cancers. Core 2 will support projects 2, 3 and Core 3 by providing them with required quantities of UAB30 and UAB110. Core 2 will also synthesize new 3rd generation rexinoids which are more potent and have an excellent safety profile. The proposed new analogs will utilize structural templates of UAB30 and UAB110, and add a limited number of substituents. The rationale for the placement of the substituents is based on our hypothesis that a ?hot-spot? in the ligand binding pocket for the rexinoid is important to initiate lipid biosynthesis. In the design of new rexinoids, the Synthetic Core will employ x-ray crystallography, and quantum mechanical calculations.
. Preventive options to combat the incidence of NMSC are of high interest. The rexinoids developed by our group are highly effective in preventing cancers. The chemistry core 2 will provide synthetic services to projects 1, 2, 3 and core 3.
