SP1-independent inhibition of FOXM1 by modified thiazolidinediones.

SP1-independent inhibition of FOXM1 by modified thiazolidinediones. Eur J Med Chem. 2020 Oct 10;:112902 Authors: Tabatabaei Dakhili SA, Pérez DJ, Gopal K, Haque M, Ussher JR, Kashfi K, Velázquez-Martínez CA Abstract This research article describes an approach to modify the thiazolidinedione scaffold to produce test drugs capable of binding to, and inhibit, the in vitro transcriptional activity of the oncogenic protein FOXM1. This approach allowed us to obtain FOXM1 inhibitors that bind directly to the FOXM1-DNA binding domain without targeting the expression levels of Sp1, an upstream transcription factor protein known to activate the expression of FOXM1. Briefly, we modified the chemical structure of the thiazolidinedione scaffold present in anti-diabetic medications such as pioglitazone, rosiglitazone and the former anti-diabetic drug troglitazone, because these drugs have been reported to exert inhibition of FOXM1 but hit other targets as well. After the chemical synthesis of 11 derivatives possessing a modified thiazolidinedione moiety, we screened all test compounds using in vitro protocols to measure their ability to (a) dissociate a FOXM1-DNA complex (EMSA assay); (b) decrease the expression of FOXM1 in triple negative-breast cancer cells (WB assay); (c) downregulate the expression of FOXM1 downstream targets (luciferase reporter assays and qPCR); and inhibit the formation of colonies of MDA-MB-231 cancer cells (colony fo...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research