Computer-aided drug discovery of Myc-Max inhibitors as potential therapeutics for prostate cancer

Abstract

While Myc is an essential regulator of growth in normal cells, it is also frequently associated with cancer progression, therapy-resistance and lethal outcomes in most human cancers. In prostate cancer (PCa), Myc transcription factors are implicated in the pathogenesis and progression of the full spectrum of PCa, from adenocarcinoma to advanced castrationresistant and neuroendocrine phenotypes. Though a high-value therapeutic target, clinically approved anti-Myc drugs have yet to be discovered. To elicit its oncogenic effects, Myc must form a heterodimer with its partner Max, which together bind DNA and activate transcription of a spectrum of target genes that promote cell growth, proliferation, metabolism,

ETS transcription factors as emerging drug targets in cancer

“…Those target proteins mostly belong to the families of G protein‐coupled receptors, kinases, ion channels, and nuclear receptors . Recent advancements in computational methods of drug discovery and deep learning, as well as exponential growth of available small molecules, make it possible to expand such limited repertoire of drug targets and to consider proteins that have traditionally been deemed as “undruggable.” Our own recent efforts demonstrated that the use of methods of Computer‐Aided Drug Design (CADD) allowed for development of potent and selective inhibitors binding to previously unattended surface‐exposed pockets of such prominent cancer targets as androgen receptor, estrogen receptor, MYC, and ERG (ETS‐related gene) …”

Lytic Induction Therapy against Epstein–Barr Virus-Associated Malignancies: Past, Present, and Future

“…Other compounds that target the DNA binding domain of the MYC–MAX complex such as KSI-3716 [ 149 ], MYCi975 [ 150 ], sAJM589 [ 151 ], and 10074-G5 [ 152 , 153 ] were found to have anti-tumor effects in multiple tumor cell types. New compounds such as PKUMDL-YC-1202-1205 [ 154 ], 7594-0035 [ 155 ], VPC70063 [ 156 ], and JKY-2-169 [ 157 ] have also been developed. It would be of interest to investigate the effects of these compounds on the reactivation of lytic cycle of EBV ( Figure 6 ).…”

“…Protein structural analyses using nuclear magnetic resonance (NMR), cryogenic electron microscopy (Cryo-EM), and crystallography as well as the increasing usage of computer programs in the prediction of active functional domains of protein and docking simulation have accelerated the progress of structure-based drug discovery [ 154 , 156 , 158 , 159 , 160 ]. For example, an EBNA1-specific probe was designed and shown to disrupt EBNA1 oligomerization and transactivation.…”

Dual-Inhibitors of N-Myc and AURKA as Potential Therapy for Neuroendocrine Prostate Cancer

“…We previously identified a potential pocket when C-Myc is associated to the homologous basic helix-loop-helix leucine zipper (bHLHLZ) domain of Max, forming a stable helical configuration which binds specifically to DNA E-boxes of targeted genes [26]. This target site is referred to as the DNA-binding domain (DBD).…”

“…The eGFP Myc transcriptional activity was assayed as previously described [26]. Briefly, cell transfection was performed using TransIT-2020 transfection reagents according to the manufacturer's instructions.…”