A Review of Molecular Predictors of Response to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer
MINI-REVIEWS IN MEDICINAL CHEMISTRY
Authors: Degener, Stephan; Mata, Douglas A.; Youssef, Ramy; Goedde, Daniel; Tandogdu, Zafer; Roth, Stephan; von Rundstedt, Friedrich-Carl
Abstract
Locally advanced, muscle-invasive urothelial carcinoma of the bladder (MIBC) may be definitively treated with either radiotherapy or radical cystectomy (RC) with urinary diversion. Neoadjuvant chemotherapy (NAC) is typically administered prior to treatment with either modality. Receiving NAC prior to RC might confer a survival advantage compared to undergoing RC alone. However, its usefulness has been questioned due to concerns about over treatment and toxicity. Having the ability to predict whether individual patients would benefit from or be harmed by NAC would be an important tool in precision medicine. Unfortunately, to date no prognostic or predictive molecular markers have been validated for this purpose. In this manuscript, we review the current state of molecular markers in MIBC treatment and outline how recent advances in whole-genome sequencing may soon improve the selection of precisely targeted therapeutics for the benefit of individual patients.
Computer-aided drug design of small molecule inhibitors of the ERCC1-XPF protein-protein interaction
CHEMICAL BIOLOGY & DRUG DESIGN
Authors: Gentile, Francesco; Elmenoufy, Ahmed H.; Ciniero, Gloria; Jay, David; Karimi-Busheri, Feridoun; Barakat, Khaled H.; Weinfeld, Michael; West, Frederick G.; Tuszynski, Jack A.
Abstract
The heterodimer of DNA excision repair protein ERCC-1 and DNA repair endonuclease XPF (ERCC1-XPF) is a 5 '-3 ' structure-specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1-XPF plays a central role in repairing DNA damage induced by chemotherapeutics including platinum-based and cross-linking agents; thus, its inhibition is a promising strategy to enhance the effect of these therapies. In this study, we rationally modified the structure of F06, a small molecule inhibitor of the ERCC1-XPF interaction (Molecular Pharmacology, 84, 2013 and 12), to improve its binding to the target. We followed a multi-step computational approach to investigate potential modification sites of F06, rationally design and rank a library of analogues, and identify candidates for chemical synthesis and in vitro testing. Our top compound, B5, showed an improved half-maximum inhibitory concentration (IC50) value of 0.49 mu M for the inhibition of ERCC1-XPF endonuclease activit, and lays the foundation for further testing and optimization. Also, the computational approach reported here can be used to develop DNA repair inhibitors targeting the ERCC1-XPF complex.