Using small molecules to overcome drug resistance induced by a viral oncogene

Abstract

We used small molecule screening to discover compounds and mechanisms for overcoming E6 oncogene-mediated drug resistance. Using high-throughput screening in isogenic cell lines, we identified compounds that potentiate doxorubicin's lethality in E6-expressing colon cancer cells. Such compounds included quaternary ammonium salts, protein synthesis inhibitors, 11-deoxyprostaglandins, and two additional classes of compounds-analogs of 1,3-bis(4-morpholinylmethyl)-2-imidazolidinethione (a thiourea) and acylated secondary amines that we named indoxins. Indoxins upregulated topoisomerase IIalpha, the target of doxorubicin, thereby increasing doxorubicin lethality. We developed a photolabeling strategy to identify targets of indoxin and discovered a nuclear actin-related protein complex as a candidate indoxin target.

Cell-Line Selectivity Improves the Predictive Power of Pharmacogenomic Analyses and Helps Identify NADPH as Biomarker for Ferroptosis Sensitivity

“…Most ferroptosis inducers were originally discovered in small molecule screening using engineered human fibroblasts (Smukste et al, 2006; Weïwer et al, 2012). Since most lethal compounds do not activate ferroptosis, we hypothesized that the GI 50 profiles of the ferroptosis inducers would be distinct from other lethal compounds.…”

Targeted therapy for the loss of von Hippel-Lindau in renal cell carcinoma: A novel molecule that induces autophagic cell death

“…Cell-based small molecule screening has been used to discover compounds that inhibit specific proteins, such as HIF, or to overcome drug resistance to reduce tumorigenicity 9-12. Recently, we used a chemical library of diverse small molecules to perform a fluorescence-based mammalian screen in wild-type VHL and VHL-deficient RCCs that were stably transfected with EYFP (manuscript in preparation).…”

A Molecule Targeting VHL-Deficient Renal Cell Carcinoma that Induces Autophagy

“…Cell-based small molecule screening has been used to discover compounds that inhibit specific proteins, such as HIF, or to overcome drug resistance to reduce tumorigenicity (Isaacs et al, 2002; Mabjeesh et al, 2003; Rapisarda et al, 2002; Smukste et al, 2006). In this report, we describe a small molecule, STF-62247, identified from a screen that induces autophagy and selectively induces lethality in RCCs that have lost the VHL tumor suppressor gene.…”