Mechanism of Retinoid X Receptor Partial Agonistic Action of 1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic Acid and Structural Development To Increase Potency

Abstract

We have reported that retinoid X receptor (RXR) partial agonist 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid (CBt-PMN, 4a) shows a significant antidiabetes effect in the KK-A(y) type 2 diabetes model mice, with reduced side effects compared to RXR full agonists. To elucidate the mechanism of the RXR partial agonist activity of 4a, we synthesized derivatives of 4a, evaluated their RXR agonist activity, and performed structure-activity relationship analysis. Reporter gene assay revealed that though 6b, which possesses an amino group at the 2-position of 5-carboxybenzimidazole, showed RXR full-agonist activity, compounds 6d and 6e, which possess an oxygen atom and a sulfur atom at the corresponding position, respectively, showed weak RXR agonist activity. On the other hand, 6c, which has a trifluoromethyl group at the corresponding position, acts as an RXR partial agonist, having similar Emax (67 ± 2%) and lower EC50 (15 ± 0 nM) compared to those of 4a (Emax = 75 ± 4%, EC50 = 143 ± 2 nM). A fluorescence polarization assay of cofactor recruitment confirmed that fluorescein-labeled D22 coactivator peptide was less efficiently recruited to RXR by 4a and 6c than by LGD1069 (1), a known RXR full agonist. Electrostatic potential field calculations and computational docking studies suggested that full agonists show an electrostatic attraction, which stabilizes the holo structure and favors coactivator recruitment, between the side chain at the benzimidazole 2-position and the α-carbonyl oxygen of asparagine-306 in helix 4 (H4) of the RXR receptor. However, RXR partial agonists 4a and 6c lack this interaction. Like 4a, 6c showed a significant antidiabetes effect in KK-A(y) type 2 diabetes model mice with reduced levels of the side effects associated with RXR full agonists. These findings should aid the design of new RXR partial agonists as antitype 2 diabetes drug candidates.

The novel rexinoid MSU-42011 is effective for the treatment of preclinical Kras-driven lung cancer

“…However, MSU-42011 had better single agent activity than bexarotene for treating established Kras-driven lung adenocarcinomas. Our data and other studies 44,58,59 confirm that these biological activities can be separated. The majority of preclinical studies have tested rexinoids in models of breast cancer 20 .…”

Designed Spiroketal Protein Modulation

“…Our work includes a rare co‐crystal structure of a spiroketal, which is to the best of our knowledge the first of a benzannulated spiroketal bound to a protein target. We believe that the apparent RXR partial agonist behavior of our spiroketal contributes to establishing partial agonism as a concept for RXR . Furthermore, the high structural homology of the LBP across the NR superfamily, combined with the structural versatility of spiroketals, suggests that spiroketals can be designed to selectively target other NR subtypes as forerunner to the designed modulation of other protein targets.…”

The Disappearing Director: The Case of Directed N‐Arylation via a Removable Hydroxyl Group

“…Among these, the tetrahydronaphthalene derivative is a ligand for retinoid X receptors, and showed significant activity against type-2 diabetes in vivo . [5] The pyrimidine-benzotriazole conjugates were shown to be potent inhibitors of JNK1 (mitogen-activated protein kinase 1), with selectivity over JNK2. [6] The acridine derivatives showed antibacterial activity, comparable to ampicillin, against S. areus , B. subtilis , and E. coli .…”