#1108 UAB30 is a RXR selective retinoid that has shown excellent activity in preventing chemically-induced mammary cancers with minimal toxicity (specifically not increasing serum triglycerides), and is currently undergoing a Phase I clinical trial. Several methyl analogs were synthesized in an attempt to obtain a more active preventive agent and to better understand the mechanisms of activity/toxicity of this class of agents. The retinoids included 4-methyl-UAB30, 5-methyl-UAB30, 6-methyl-UAB30, 7-methyl-UAB30, and 8-methyl-UAB30. The compounds were evaluated in the MNU-induced mammary cancer model using female Sprague-Dawley rats. MNU (75 mg/kg BW) was administered at 50 days of age and the animals observed for 120 days afterward for the development of ER+ mammary cancers. The retinoids were given at a dose of 200 mg/kg diet, except 7-methyl-UAB30 (given at 100 mg/kg diet). 4-Methyl-UAB30 and 7-methyl-UAB30 were highly active; reducing mammary cancer multiplicity by 74 and 61%, respectively. The retinoids 5-methyl-UAB30, 6-methyl-UAB30, and 8-methyl-UAB30 did not have chemopreventive activity in this model. The 8-methyl-UAB30 derivative actually caused a 108% increase in growth of the mammary cancers. As we have previously shown (Carcinogenesis 27, 1232-1239, 2006), serum triglycerides correlated with cancer preventive activity; i.e., high levels were observed with active retinoids. 4-methyl-UAB30 caused an initial large increase in body weight gain of the rats. Of interest, serum levels of 6-methyl-UAB30 and 7-methyl-UAB30 were high, while the other agents were low or could not be detected. All methyl derivatives caused varying decreases in liver retinyl palmitate levels. Structure-activity relationships are also being evaluated using crystallography of RXR/UAB-rexinoid complexes as a guide. Structure-based and dynamic-based approaches are used to facilitate the design of new rexinoids that fit into the LBD of RXRs. For example, 4-methyl-UAB30 had a 5-fold greater binding affinity to hRXR alpha LBD than 9-cis-retinoic-acid. These studies emphasize that minor modifications of a retinoid molecule can drastically change its absorption, metabolism, toxicity, binding affinities to receptors, and activity in preventing mammary cancers. (Supported by NCI Breast SPORE CA089019 and contract HHSN261200433001C). Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1108.
1 Dermatology Discovery (DZR12), Abbvie, North Chicago, IL and 2 Immune Pharmacology/ Translations (RD20), Abbvie, Boston, MA IL-23 is a key cytokine contributing to the development of Th17 cells and is critical to the pathogenesis of psoriasis. We evaluated two models of IL-23-induced psoriasiform dermatitis in mice. Psoriasis-like skin lesions were induced by either intradermal ear injection of IL-23 to C57BL/6 mice (IL-23 ear injection model) or by tail vein delivery of IL-23 minicircles (MC) to B10.RIII mice (IL-23 MC model). Biologically, these models differ by their either localized or systemic distribution of IL-23 and were compared for disease pathology and cytokine levels. Plasma levels of IL-23 after MC delivery were increased to 6-15 ng/mL from levels below detection and coincided with increases in ear swelling and epidermal thickening as early as day-7 post injection. Evidence of a more systemic pathology was also observed (e.g., paw and joint swelling). Local IL-23 increased ear swelling and epidermal thickness in a dose-and time-dependent manner, with epidermal thickness increasing 3-fold after 4 doses of IL-23 (1 mg, QD). Expression of key cytokines (IL-17A, IL-17F, IL-22, IL-6, and TNF-a, MCP-1) was elevated (P<0.05) in a time-dependent manner in-injected ears. Ear swelling and/or epidermal hyperplasia was significantly reduced by treatments with Apremilast (30 mpk, P<0.05), anti-IL17A mAb (12 mg/kg, P<0.01), anti-TNF-a mAb (10 or 15 mg/kg, P<0.05), and anti-p40 mAb (15 or 50 mg/kg, P<0.01). Interestingly, Apremilast efficacy dissipated in a more chronic (9-day) model of IL-23 ear injections differentiating this mechanism from the others. The IL-23 MC model clearly demonstrates psoriasiform changes in skin but also other comorbidities and will be further evaluated. The acute IL-23 ear injection model is useful to evaluate psoriasis drug targets downstream of the IL-23 pathway and the more chronic IL-23 ear model may highlight mechanistic differences for both drug mechanism of action and disease pathology.
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