Development of Potent and non-toxic rexinoids to prevent non-melanoma skin cancer - Abstract: Non-melanoma skin cancer (NMSC), which include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) is one of the most common types of cancers in the US. Due to compromised immunity, solid organ transplant recipients (SOTRs) are at a much higher risk for NMSC and it often becomes the cause of death in SOTRs. Prevention of NMSC is an ideal strategy, particularly for immune compromised populations. Rexinoids are small molecule drugs and are able to prevent skin cancer. However, some of the adverse effects may lead to non-compliance in their use. We have developed two distinct classes of structures of rexinoids: UAB30 and UAB20, which are highly selective, non-toxic and orally bioavailable RXR agonists. These agents are also highly effective in preventing skin cancer as shown in our preliminary data. Both UAB30 and UAB20 do not cause hyperlipidemia, an effect usually associated with clinically approved rexinoids. Dampening cancer associated inflammatory biomarkers is also an attractive property of these agents. Thus, our enthusiasm for further developing highly effective analogs of these agents as cancer chemopreventive agents has prompted us to submit this proposal. Guided by x-ray crystallography and biophysical studies, we propose to develop novel analogs of UAB30 & UAB20 with enhanced potency than parent compounds, with suitable pharmacokinetics for chronic administration and without any overt toxicity. Low energy molecular conformation of UAB30 fit well into the RXR ligand-binding pocket (LBP). Our strategy is to improve the potency significantly without distorting the molecular conformations of these two agents. Therefore, we propose to substitute a hydrogen atom with a halogen and/or a heteroatom. Because of the electronegativity of fluorine and the strength of carbon-fluorine bond, we have reasoned that strategic introduction of fluorine will improve the potency, oral bioavailability, metabolic stability and pharmacokinetics of the newly synthesized analogs. Heteroatoms such as nitrogen can modulate the polarity (logP) value significantly. Therefore, we have proposed to substitute a single carbon of tetralone ring of the UAB30 with a nitrogen. Individually and collectively, these modifications will significantly contribute to the potency of UAB30 analogs and will make them ideal agents for pre-clinical evaluation. Similarly, for UAB20, x-ray crystal structures reveal that a five membered heterocyclic ring is accommodated more favorably and make interactions within the LBP. Therefore, we have proposed to substitute the phenyl ring with heterocyclic rings. These modifications will also modulate the logP and improve pharmacokinetics of these new analogs. Our co-investigator in this application has developed unique murine models of the NMSC, which recapitulate human pathobiology of the disease both in normal population and in SOTRs. These models will be employed in the proposed investigations to define the most effective and non-toxic analogs suitable for chronic administration for NMSC chemoprevention. During this grant period, we expect to develop at least one new rexinoid ready for clinical development after GLP toxicity evaluation.
