Identification of repositioned inhibitors of pan-cancer proteasomal target as potential anti-proliferative candidates using a computational therapeutics approach.

Abstract

UBE2C (Ubiquitin-Conjugating Enzyme E2C) is an E2 ubiquitin-conjugating enzyme involved in the ubiquitin-proteasome system which plays a crucial role in protein degradation and regulation of cell cycle. Overexpression of UBE2C can lead to mitotic defects, genomic instability and uncontrolled cell division, contributing to tumorigenesis. Overexpression of UBE2C in multiple cancers and its association with enhanced tumor progression, metastasis and drug resistance has led to its consideration as a potential therapeutic target. We report association of high UBE2C expression with poor overall survival across cancers, present p53-status-stratified expression analysis, determine its essentiality based on dependency scores in multiple cancer cell lines, association with immune cell infiltration, and analyze the effect of UBE2C silencing on cancer pathways, thus corroborating it as a viable pan-cancer target. We then identify potential UBE2C targeting repositioned therapeutics at both mRNA and protein levels by employing structure-based virtual screening, using CMap database, ceSAR based sig2lead application, and performing molecular dynamic simulations. Finally, we provide the effect of selected compounds on cell viability in NCI60 panel of cancer cell lines from different tissue origins. The compounds anisomycin, cephaeline, digitoxin, mitoxantrone, digoxin, digitoxigenin, homoharringtonine, NCI724448, midostaurin, withaferin A and NCI718581 were found to be effective UBE2C targeting candidates which could result in significant growth inhibition at low doses across multiple cell lines. Our results lay a strong groundwork for further preclinical exploration of the efficacy of these compounds against different cancers individually as also in combination with existing therapeutics for their future development as novel anticancer drugs.