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ISSN: 2165-7831
Journal of Blood & Lymph
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Targeting Protein Interactions: A Novel Therapeutic Strategy against Prostate Cancer

Preethi Ravindranathan*

Department of Urology, UT Southwestern Medical Center, Dallas, USA

*Corresponding Author:
Preethi Ravindranathan
Department of Urology
UT Southwestern Medical Center
5323 Harry Hines Blvd, Dallas
TX 75390, USA
Tel: 214-648-3363
E-mail: Preethi.Ravindranathan@UTSouthwestern.edu

Received date: March 31, 2015; Accepted date: April 03, 2015; Published date: April 13, 2015

Citation: Ravindranathan P (2016) Targeting Protein Interactions: A Novel Therapeutic Strategy against Prostate Cancer. J Blood Lymph 5:e119. doi: 10.4172/2165-7831.1000e119

Copyright: © 2015 Ravindranathan P, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Editorial

The expression and signaling of Androgen Receptor (AR) isnecessary for the development of prostate cancer, and hence, is a majortarget for pharmaceutical drug development against the disease. AR,which is predominantly present in the cytoplasm when inactive, isactivated by the binding of androgens resulting in its translocation tothe nucleus. Once in the nucleus, AR modulates the expression oftarget genes by binding to androgen-responsive elements (ARE) ontheir promoter/enhancer regions and recruiting coregulators and other proteins of the transcriptional machinery.

A critical locus of AR function is its binding to coregulators thatserve as platforms for interactions with other proteins involved invarious cellular functions including transcription, signaling and cellcycle regulation. Increase in the expression of these coregulatorproteins and their activation of AR signaling in the absence ofhormones in prostate cancer are evidences of their role in the disease[1]. Consequently, disrupting AR interactions with its coregulators bymimicking interacting ‘protuberances’ or ‘sockets’ within the bindingregions using small molecules or peptidomimetics could serve as a strategy to block AR function.

Mimicking a-helical secondary structures to block proteininteractions has an immense potential owing to their prevalence in theinteracting motifs of many therapeutically relevant proteins. The 10-12amino acids that comprise an a-helix rotate in such a way that the sidechains of i, i+3 and i+4th amino acids project out from the helix andare available for interactions with other proteins. A major subset of ARcoregulators interact with the ligand binding domain in AR throughtheir signature a-helical LXXLL motif (X is any amino acid). Peptidesmimicking LXXLL motif have previously been used to successfullyblock AR-coregulator interactions [2]. However, their use as drugs is limited due to their low cell permeability and stability.

In our paper in Nature Communications [3], we reported the use ofoligo-benzamide scaffolds to mimic a-helical LXXLL motif. Theconformationally constrained oligo-benzamide, named D2, projects itsside chains to emulate the position and angular orientation of i and i+4amino acid side chains of the LXXLL motif, thereby, disrupting ARinteractions with LXXLL-motif containing coregulator, Proline-,glutamic acid- and leucine-rich protein 1 (PELP1). The critical role ofcoregulator PELP1 in AR-mediated signaling in prostate cancer wasrecently demonstrated by Yang et al. [4]. The LXXLL-mimetic D2 wasable to disrupt AR-PELP1 interactions and AR-transcriptional function in the nM range, and its effect overcome by an overexpression of either AR or PELP1, suggesting its role as a competitive inhibitor in AR-PELP1 binding. Another convincing proof of the mimetic blocking AR signaling is that while it suppressed the growth of AR-positive cells in vitro, it had no growth-inhibitory effect on AR-negative prostate cancer cells.

Experiments done in vivo in mouse xenografts and human tumorexplant models highlight the clinical translatability of D2. Notably,intratumoral and intraperitoneal administration of D2 significantlyblocked the growth of tumor in subcutaneous C4-2 cell xenografts inSCID mice. Also, no toxicity or changes in weight were observed inthese D2-administered mice. Additionally, our coimmunoprecipitationassays revealed a decrease in interaction betweenAR and PELP1 in human prostate tumor explants cultured with D2,demonstrating the ability of the mimetic to function on prostate cancer cells in their native environment.

Although D2 can potentially inhibit a wide array of proteininteractions involving LXXLL motif, its binding specificity could beimproved by using larger oligo-benzamide scaffolds that present morebinding groups from the a-helical secondary structure. A majoradvantage of using small mimetics to block protein interactions is thatwhile they can be designed to selectively bind to specific bindingpockets in target proteins, they are less prone to proteolytic cleavageand have higher bioavailability compared to peptide mimics. Also, theease of synthesis of these oligo-benzamide-based mimetics usingsimple chemical reactions makes them very attractive from a pharmaceutical point of view [5].

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