Conformationally Defined Retinoic Acid Analogues. 4. Potential New Agents for Acute Promyelocytic and Juvenile Myelomonocytic Leukemias

Abstract

We recently synthesized several conformationally constrained retinoic acid (RA) analogues [8-(2'-cyclohexen-1'-ylidene)-3, 7-dimethyl-2,4,6-octatrienoic acids with different alkyl substituents at 2' (R1) and 3' (R2) positions on the cyclohexene ring] (Muccio et al. J. Med. Chem. 1996, 39, 3625) as cancer chemopreventive agents. UAB8 (R1 = Et; R2 = iPr), which contains sufficient steric bulk at the terminal end of the polyene chain to mimic the trimethylcyclohexenyl ring of RA, displayed biological properties similar to those of RA. To explore the efficacy of this retinoid in acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML), we evaluated UAB8 isomers in in vitro assays which measure the capacity of retinoids to inhibit aberrant myeloid colony growth from blood or bone marrow cells obtained from human JMML patients and in assays measuring the potential of retinoids to differentiate NB4 cells (an APL cell line). Both (all-E)- and (13Z)-UAB8 were 2-fold more active than RA in the NB4 cell differentiation assay; however, only (all-E)-UAB8 had comparable activity to the natural retinoids in the JMML cell assays. These results were compared to the biological effectiveness of a new retinoid, UAB30 [8-(3', 4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4, 6-octatrienoic acid], which had different nuclear receptor binding and transactivational properties than UAB8. Relative to (all-E)-RA and (all-E)-UAB8, (all-E)-UAB30 bound well to RARalpha but did not activate transcription-mediated RARalpha homodimers, even though it was effective in RARbeta- and RARgamma-mediated transactivational assays. In APL assays, this retinoid had much reduced activity and was only moderately effective in JMML assays and in cancer chemoprevention assays.

Defining the Communication between Agonist and Coactivator Binding in the Retinoid X Receptor α Ligand Binding Domain

“…We have demonstrated that 9cUAB30 compared well with Targretin in its capacity to prevent mammary cancer (21)(22)(23)(24)(25). The in vitro studies presented here also show how similar each rexinoid is in blocking ErbB2-oncogenic transformation, consistent with in vivo studies.…”

“…Materials-9cUAB30 was synthesized at the University of Alabama at Birmingham according to previous methods (21,24). Targretin was provided by Dr. Clinton Grubbs at UAB.…”

“…Previous reports have shown that 9cRA, Targretin, and 9cUAB30 are potent agonists of RXR␣ transcription (2,14,21). Here we compared each RXR agonist for its capacity to inhibit oncogenic transformation of rat kidney epithelial (RK3E) cells.…”

“…Although 9cUAB30 is slightly less potent than Targretin or 9cRA, it displays a higher degree of RXR selectivity. 9cUAB30 has also been shown to be effective in cancer prevention models (21)(22)(23)(24)(25). 9cUAB30 is a tissue-selective RXR agonist; it does not act as an agonist in liver to activate lipid biosynthesis although it has agonist capabilities in cancer cells (26).…”

Effects on Gene Expression in Rat Liver after Administration of RXR Agonists: UAB30, 4-Methyl-UAB30, and Targretin (Bexarotene)

“…However, the elevation of triglycerides levels by 9-cis-RA, TRG, and various retinoids has been known for many years and is a major concern in the use of these agents, particularly in a cancer-prevention setting (Grubbs et al, 2006;Kolesar et al, 2010). We previously designed selective RXR agonists based on 9-cis-RA that are effective agents with lower toxicity and with varying ability to inhibit mammary cancer formation (Muccio et al, 1998;Atigadda et al, 2003;.Grubbs et al, 2006). One of these analogs (UAB30) did not increase serum triglycerides in rodents (Grubbs et al, 2006) and humans (Kolesar et al, 2010) but was nevertheless effective in preventing mammary cancers in rats.…”