In a study published recently in ACS Chemical Biology, a University of Kansas research team (KA, USA) have identified the first reported small-molecule HuR inhibitors. The ground-breaking proof-of-principle study is the first of its kind to demonstrate that HuR is druggable, and could lead to a new class of cancer drugs with the potential to treat a range of cancers including colon, prostate, breast, brain, ovarian, pancreatic and lung cancer.
HuR has been detected at high levels in almost every type of cancer tested and is involved in many stem cell pathways. Until now, no direct HuR inhibitors have been discovered. The team’s newly-identified HuR inhibitors work by competitively disrupting HuR-RNA binding to enable the release of RNA. This in turn blocks the HuR ‘oncoprotein’ function.
Across 3 ½ years of research, approximately 6000 compounds from both the University of Kansas Chemical Methodologies and Library Development Center (KS, USA) and the FDA were evaluated by high-throughput screening, in which compounds that obstruct HuR’s interface with healthy human RNA were identified.
The most promising compounds with which to to target the HuR oncoprotein were chosen using Amplified Luminescent Proximity Homogeneous Assays, surface plasmon resonance, ribonucleoprotein immunoprecipitation assays and luciferase reporter functional studies. Six compounds, each with a similar chemical structure, were identified as starting points of novel HuR targeting drugs.
Liang Xu (University of Kansas), corresponding author of the paper, reported that the HuR-RNA binding site is similar to a long, narrow groove, and is not well-defined like other druggable proteins targeted in many current cancer therapies: “HuR tightly binds to RNA like a hand. The HuR protein grabs the ‘rope’ – or the RNA – at a site called ‘ARE’ on the rope. We aimed to find a small-molecule compound that makes the hand release the rope by competing with ARE of the RNA.”
Devoted to a career in cancer research and drug discovery, Xu is committed to translating discovery in the lab into clinical therapy, to help cancer patients: “The initial compounds reported in this paper can be further optimized and developed as a whole new class of cancer therapy, especially for cancer stem cells.”
In verifying that HuR is druggable, the reseach team’s proof-of-principle study opens a new door for cancer drug discovery. Moreover, many other ‘undruggable’ RNA-binding proteins similar to HuR, could also be tested for drug discovery using similar methods.
Sources: Wu X, Lan L, Michael D et al. Identification and validation of novel small molecule disruptors of HuR-mRNA interaction. ACS Chemical Biology; 150317154550000 DOI: 10.1021/cb500851u (2015); University of Kansas press release