Abstract 5881: Novel inhibitors of the epigenetic reader protein MBD2

Abstract

DNA hypermethylation can trigger silencing of tumor suppressor genes during cancer development and progression, partly through binding by methylated-DNA binding proteins (MBD), such as MBD2, that function as “epigenetic readers” and recruit co-repressor complexes to promote gene repression. Inhibiting MBD2-mediated repression represents an attractive cancer therapeutic strategy. Here, we used a cell-based screen to identify small molecules capable of reactivating hypermethylated promoter sequences. We used biochemical, molecular biologic, and pharmacologic approaches to characterize mechanism of action of identified MBD2 inhibitors. A subset of these compounds represent a new class of inhibitors capable of selectively antagonizing interactions between MBD2 and methylated DNA, leading to reactivation of the hypermethylated gene GSTP1 and the epigenetically silenced retinoic acid signaling pathway. Combinations of one of the newly identified MBD2 inhibitors, KCC-08, with the retinoic acid receptor agonist, isotretinoin, significantly reduced cancer cell growth/survival in vitro and in vivo. These novel MBD2 inhibitors are thus positioned for further pharmacologic lead development for use as probes to interrogate epigenetic gene silencing mechanisms and as cancer therapeutics. Citation Format: Hugh Giovinazzo, Zachary R. Reichert, Andries Bergman, Xiaohui Lin, Nicolas Wyhs, David Esopi, Ajay Vaghasia, Jianyong Liu, Yash Jain, Akshay Bhamidipati, Ruchama Steinberg, Traci Speed, Matthew Vaughn, Yonggang Zhang, Nate Brennen, Theodore Deweese, Srinivasan Yegnasubramanian, William G. Nelson. Novel inhibitors of the epigenetic reader protein MBD2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5881.

Expression and clinical significance of methyl‑CpG binding domain protein 2 in high‑grade serous ovarian cancer

“…Sequence-specific antisense MBD2 inhibitors suppress the anchorage-independent growth of human tumor cell lines in vitro and the growth of human tumor xenografts in vivo (52). The newly discovered MBD2 inhibitor KCC-08 combined with the retinoic acid receptor agonist isoretinoic acid can significantly reduce the growth and survival of cancer cells (53). However, the present study had some limitations, such as a small sample size and the nature of the study as a single-center study.…”

A Comprehensive In Silico Perspective For Discovery of Novel Inhibitory Candidates Targeting Versatile Transcriptional Repressor MBD2

“…Although the structure of MBD2 and its function in several biological processes and disease progression have been well-characterized suggesting as key targets, the number of available inhibitors against that epigenetic regulator is still barely limited and therefore submission of novel potential ones maintains its importance yet. To date, NF449, Mitoxantrone, Idarubicin, Aurintricarboxylic acid have been proposed as preventing MBD2 from methylated DNA binding (Wyhs et al, 2014), and KCC-07 (commercially available) and KCC-08 have been biologically tested in vitro and/or in vivo (Giovinazzo et al, 2018;D. Zhu et al, 2018).…”