Modeling, synthesis and cell-based evaluation of pyridine-substituted analogs of CD3254 and fluorinated analogs of CBt-PMN as novel therapeutics

• Published in: Bioorganic & medicinal chemistry 2025-01, p.118059, Article 118059
• Main Authors: Jurutka, Peter W., Khan, Zainab, Kaneko, Ichiro, Sausedo, Michael A., Shahani, Pritika H., MacNeill, Mairi, Grozic, Aleksandra, Bhogal, Jaskaran, Sweirski, Johnathon, Wentzel, Michael R., Chhun, Christine, Applegate, Michael T., Raban, San, Ibrahim, Samir, Alwaeli, Karar, Feldman, Tracie L., Pomeroy, Kayla J., Sarnowski, Joseph T., Nguyen, Natalia, Ziller, Joseph W., Ma, Ning, van der Vaart, Arjan, Hackney, Jennifer F., Marshall, Pamela A., Wagner, Carl E.
• Format: Article
• Language: English
• Subjects: Leukemia; Retinoid; Retinoid-X-receptor; Small molecule therapeutic; Structure–activity-relationship
• ISSN: 0968-0896
• DOI: 10.1016/j.bmc.2024.118059

[Display omitted] •Six pyridine analogs of CD3254 demonstrate a range of retinoid X receptor activity that depends on the position of the nitrogen atom in the pyridine ring compared to bexarotene.•Fluorinated analogs of CBt-PMN possess lower activity than their non-fluorinated, parent compounds.•Principle Component Analysis (PCA) helps visualize compound activity variance.•Two pyridine analogs of CD3254 with similar activity as bexarotene exhibited lower SREBP and RAR activity than bexarotene. Six pyridine analogs of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid—or CD3254 (11)—in addition to two novel analogs of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (CBt-PMN or 23) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), an FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Treatment with 1 often elicits side-effects by disrupting or provoking other RXR-dependent nuclear receptors and cellular pathways. All analogs were assessed through modeling for their ability to bind RXR and then evaluated in human colon and kidney cells employing an RXR-RXR mammalian-2-hybrid (M2H) system and in an RXRE-controlled transcriptional assay. The EC50 values for these analogs, and their corresponding effectiveness in activating both LXR/LXRE and the Sterol Regulatory Element Binding Protein (SREBP) promoter in comparison to 1, suggests that these compounds likely display a range of therapeutic potential and differential side effect profiles. Several analogs also exhibited reduced retinoic-acid-receptor (RAR) cross-signaling implying that they possess enhanced selectivity towards activation of cellular RXR versus RAR pathways. These results show that modifying potent rexinoids such as CD3254 or partial agonists such as CBt-PMN can result in improved target receptor selectivity and enhanced potency, such as compounds 26, 27 and 28 in this study, compared with approved therapeutics such as compound 1, where these three compounds exhibited similar potency as 1, but 26 and 27 lower RAR and SREBP activation than 1.