Biology subjects

Poyya, J.

Publications and source records attributed to Poyya, J..

3 recordsLinked to original sources

bioRxiv2024

Inhibition of the HSP90 homodimerization and HSP90-HIF1α interactions by employing small molecules at C-terminal ATP binding site of HSP90

The Heat shock protein HSP 90-alpha (HSP90AA1) is a major chaperone that stabilizes the hypoxia-inducible factor 1 under hypoxic stress and develops solid tumors. Recent studies revealed that in addition to N-terminal ATP binding site, HSP90 has an additional ATP binding site at the C-terminal end. So, disruption of HSP90 and HIF 1 interaction is an innovative method to control cancer progression. This can be achieved by employing small molecules at C-terminal ATP-binding that do not affect the overall functioning of the HSP90. But there is a lack of structural basis for HIF-1 and HSP90AA1 interactions. This study screened natural products and their derivatives against HSP90AA1 and HIF-1 interaction disruption. Virtual screening was carried out using Glide. We found that compounds with indole rings bind to the C-terminal ATP binding site of HSP90 and prevent its interaction with HIF-1. Tryptamine derivatives with indole rings showed a greater binding affinity than other molecules. Thus, Tryptamine hydrochloride compounds can be used as a drug repurposing approach to treat hypoxic tumors. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/595921v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1d2d547org.highwire.dtl.DTLVardef@b03175org.highwire.dtl.DTLVardef@17f0d31org.highwire.dtl.DTLVardef@3b30a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Ellagic acid: a potential inhibitor of enhancer of zeste homolog-2 and protein arginine methyltransferase-5

Dysregulation of epigenetic processes, characterized by aberrant DNA methylation patterns and histone modifications, is a hallmark of cancer, driving its initiation, progression, and metastasis by silencing tumor suppressor genes or activating oncogenes. Perturbations in histone modifications such as H3K27me3 by EZH2 and H4R3me2s by PRMT5 play significant roles in these epigenetic alterations, disrupting normal gene expression and facilitating oncogene activation while suppressing tumor suppressor genes. Consequently, inhibitors targeting enzymes involved in DNA methylation, histone modification, or chromatin remodeling, such as PRMTs and PRC complexes, are promising anti-cancer agents, with several undergoing pre-clinical and clinical trials. Our screening of a phytochemical library revealed ellagic acid as an effective inhibitor of both EZH2 and PRMT5. Ellagic acid interacts strongly with the EZH2 and PRMT5:MEP50 complex, binding to their active sites through {pi}-cation interactions and hydrogen bonds. Surface Plasmon Resonance study confirmed potent binding affinities of ellagic acid, with KD values of 3.28E-06 and 6.54E-05 for EZH2 and PRMT5:MEP50 respectively. In-vitro assays validated inhibitory effects on EZH2 and PRMT5:MEP50 by reducing the levels of their catalytic products H3K27me3 and H4R3me2s respectively and induction of autophagy and apoptosis. Further In-vivo studies using mouse xenografts further demonstrated significant tumor size reductions upon oral administration of ellagic acid, with decreased expression of the proliferative marker ki67 and histone repressive marks. Taken together we showed that inhibition of EZH2 and PRMT5:MEP50 by ellagic acid could be used to develop breast cancer therapeutic drug.

cancer biology↗

bioRxiv2024

Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer both in vitro and in vivo

Histone methyltransferases are selectively catalyzing the methylation of lysine or arginine residues of target histone and non-histone proteins, classified as lysine methyltransferases and arginine methyltransferases. The EZH2 and PRMT5 catalyze trimethylation of H3 at K27 and symmetric dimethylation of H4 at R3 respectively. These histone repressive marks have been considered as hallmarks in cancer. Both PRMT5 and EZH2 over expressed in several cancers and have been considered as important target of drug development. As a result, many synthetic molecules as inhibitors of both PRMT5 and EZH2 are at different level of preclinical and clinical phases. Cancer atlas data analysis revealed that both PRMT5 and EZH2 had shown more than 90% amplification in breast cancer alone. We screened an array of phytocompounds towards the inhibition of PRMT5 and EZH2 using in silico, in vitro assays. Among them Epigallocatechin-3-gallate (EGCG) has interacted with human PRMT5: MEP50 and EZH2 efficiently. The EGCG interacted within the SAM binding site, with a {pi}-cation interaction at Lys 333 and H-bonds with Tyr324, Tyr334, Gly365, Leu437, and Glu444. Surface plasmon resonance analysis revealed that EGCG has strong binding affinity in nanomolar concentrations with both PRMT5-MEP50 than EZH2. Further in vitro methylation and cell-based assays proved the inhibitory potential of EGCG by reducing the catalytic products of PRMT5 and EZH2 i.e., H4R3me2s & H3K27me3 respectively and showed that it induced autophagy and apoptosis. Furthermore in vivo, mouse xenografts studies demonstrated that oral dosage, reduced tumor size significantly with reduction in proliferation marker Ki67 and these histone repressive marks. Finally conclude that inhibition of PRMT5 and EZH2 by EGCG potentially can be used to develop combined therapeutic approaches.

cancer biology↗