The era of high-quality chemical probes.

Small-molecule chemical probes are among the most important tools to study the function of proteins in cells and organisms. Regrettably, the use of weak and non-selective small molecules has generated an abundance of erroneous conclusions in the scientific literature. More recently, minimal criteria have been outlined for investigational compounds, encouraging the selection and use of high-quality chemical probes.

A New Chemical Probe Challenges the Broad Cancer Essentiality of CK2.

Casein kinase 2 (CK2) is highly expressed in cancer and has been considered a potential therapeutic target. Wells and colleagues developed and characterized the new CK2 inhibitor SGC-CK2-1. Unexpectedly, this potent and highly selective chemical probe does not show broad antiproliferative activity in cancer cells.

Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma.

The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription.

Mapping the perturbome network of cellular perturbations.

Drug combinations provide effective treatments for diverse diseases, but also represent a major cause of adverse reactions. Currently there is no systematic understanding of how the complex cellular perturbations induced by different drugs influence each other. Here, we introduce a mathematical framework for classifying any interaction between perturbations with high-dimensional effects into 12 interaction types.

A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor.

Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies.

Pharmacological treats for SUMO addicts.

Non-oncogene addiction exploits cancer vulnerabilities resulting from altered cellular signaling pathways in response to oncogenic mutations that are not directly druggable. In this perspective, we address recent findings showing how the SUMOylation cascade provides a synthetic lethal target in the context of different malignant transformations. Functional genomics screens have revealed that the activation of oncogenes such as NOTCH1, MYC or KRAS generates a cancer-specific dependency on SUMOylation.

Peptide nucleic acid molecular beacons for the detection of PCR amplicons in droplet-based microfluidic devices.

The use of droplet-based microfluidics and peptide nucleic acid molecular beacons for the detection of polymerase chain reaction (PCR)-amplified DNA sequences within nanoliter-sized droplets is described in this work. The nanomolar-attomolar detection capabilities of the method were preliminarily tested by targeting two different single-stranded DNA sequences from the genetically modified Roundup Ready soybean and the Olea europaea genomes and detecting the fluorescence generated by peptide nucleic acid molecular beacons with fluorescence microscopy. Furthermore, the detection of 10 nM solutions of PCR amplicon of DNA extracted from leaves of O.