Biology subjects

Oyelere, A. K.

Publications and source records attributed to Oyelere, A. K..

3 recordsLinked to original sources

bioRxiv2026

Dual-acting Estrogen Receptor Modulator-Histone Lysine Demethylase Inhibitors

Epigenetic dysfunction and the malfunction of endocrine proteins such as estrogen receptor alpha (ER) are two key mechanisms for the sustenance of breast carcinoma. Agents that target ER signaling malfunctions are standard therapies for ER-dependent breast cancer (BCa) subtypes. Small molecule inhibitors of epigenetic modifiers, histone lysine demethylases (KDMs), have shown promise as therapeutic agents for several BCa subtypes. We demonstrated herein that the integration of ER antagonist (Tamoxifen) and agonist (17-ethinylestradiol) ligands with deferiprone (DFP)-derived KDM inhibitor moiety furnished dual-acting agents Tam-KDMi and EED-KDMi, respectively. These agents showed robust on-target effects and potent BCa cells-selective anti-proliferative activities. The Tam-KDMi are cytotoxic to both ER(+) and ER(-) BCa cells, while the lack of ER-signaling inhibition conferred an enhanced ER(-) cells cytotoxic to the EED-KDMi. Representative lead compounds Tam-KDMi DW-116 and EED-KDMi DW-088 and DW-95 significantly reduce tumor growth in murine xenograft models of ER(-) and ER(+) BCas with TGI as high as 70%. Collectively, our data showed that DW-116, DW-088 and DW-95 have a high potential as leads for the development of new agents for the treatment of BCa subtypes regardless of the tumor ER expression status.

cancer biology↗

bioRxiv2025

Transcriptomic Signature and PROTAC Strategy Revealed Histone Lysine Demethylase as a Target of Anticancer Activity of Deferiprone.

Deferiprone (DFP) is an iron chelator approved for treating iron overload in thalassemia patients. Recent observations have suggested that DFP has promising anticancer activities ascribed to several mechanisms including reduction of the intracellular free labile iron and zinc ion pools and inhibition of the activities of other intracellular targets, including ribonucleotide reductase (RNR). We previously reported that DFP inhibits the demethylase activities of several Fe(II)/- ketoglutarate dependent histone lysine demethylases (KDMs) at much lower concentrations at which it inhibits RNR activities and/or reduces the labile intracellular iron and zinc ion pools. In this study, we used RNA sequencing (RNA seq) and PROTACs strategies to validate and quantify the contribution of intracellular KDM inhibition to the antiproliferative activities of DFP. We report herein that DFP elicited gene expression signature that is largely similar to that of JIB-04, an established KDM inhibitor (KDMi), in two breast cancer (BCa) cells (MCF-7 and MDA-MD-231). Importantly, RNA seq revealed that DFP and JIB-04 downregulated the expression of hypoxia-inducible factor 1 (HIF-1), an oncogene whose expression is commonly modulated through histone demethylation mediated by KDMs and degraded by several KDMi. Moreover, DFP-derived PROTACs elicited enhanced cancer cell selective antiproliferative activities and intracellular on-target effects, downregulating several KDMs implicated in the etiology of BCa cells, including a strong degradation of KDMs 2A, 3A and 5B, and a moderate degradation of KDMs 4A-C, 5C, 6B. Collectively, our data supports KDM inhibition as a key mechanism of anticancer activity of DFP and identifies PROTAC is a viable strategy to obtain novel DFP analogs with improved potency and therapeutic index.

cancer biology↗

bioRxiv2024

A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective Against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy

Hepatocellular cancer (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylases (HDACs) activation. However, inhibiting HDACs -- an effective treatment for lymphomas -- has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells. The lead compound STR-V-53 (3) showed a favorable safety profile in mice and robustly suppressed tumor growth in orthotopic xenograft models of HCC. When combined with the anti-HCC drug sorafenib, STR-V-53 showed greater in vivo efficacy. Moreover, STR-V-53 combined with anti-PD1 therapy increased the CD8+ to regulatory T-cell (Treg) ratio and survival in an orthotopic HCC model in immunocompetent mice. This combination therapy resulted in durable responses in 40% of the mice. Transcriptomic analysis revealed that STR-V-53 primed HCC cells to immunotherapy through HDAC inhibition, impaired glucose-regulated transcription, impaired DNA synthesis, upregulated apoptosis, and stimulated the immune response pathway. Collectively, our data demonstrate that the novel HDACi STR-V-53 is an effective anti-HCC agent that can induce profound responses when combined with standard immunotherapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/587062v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@28281corg.highwire.dtl.DTLVardef@617aa9org.highwire.dtl.DTLVardef@1bc198dorg.highwire.dtl.DTLVardef@31852e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗