ASK1 is one of the key mediators of the cellular stress response and modulation of this pathway with the ATP-competitive inhibitor, Selonsertib, is being tested in the clinic for the treatment of liver fibrosis. To test the therapeutic value of inhibiting ASK1 in neurological disease, we have identified novel ASK1 brain-penetrant inhibitors using a structure-based drug design approach. The results from this effort will be presented.

AssayQuant® has combined chelation-enhanced fluorescence, using the sulfonamido-oxine (Sox) chromophore, with high-throughput peptide synthesis methods to identify optimized, physiologically based substrates for measuring the activity of protein kinases and phosphatases. The result is a simple, yet powerful method that allows continuous, quantitative, and homogenous detection of activity using recombinant enzymes or crude cell or tissue lysates. This approach provides a quantum improvement in assay performance and productivity needed to accelerate discovery and drug development efforts.

Cyclin-dependent kinases (CDKs) regulate the cell-division and RNA polymerase II-dependent transcription cycles. Transcriptional CDKs have recently emerged as potential therapeutic targets in cancer, but deeper understanding of their functions and interactions is needed to guide new drug discovery and development. Through chemical genetics, we identified novel substrates of a transcriptional CDK, Cdk9, and uncovered distinct Cdk9-phosphatase switches that govern key transitions at the beginning and end of the transcription cycle.

The design of kinase inhibitors for neurological indications is challenging because of limits in physicochemical properties that compounds should have in order to be brain penetrant. Models were developed for predicting P-gp- and BCRP-mediated efflux and Kpuu. The talk will overview the performance of these models and the physicochemical properties that brain penetrant kinase inhibitors have.

We introduce SAR by Space, a concept to drastically accelerate SAR elucidation. Hits from the REAL Space were combi-docked into the binding site of BRD4, thus avoiding time-consuming simulations. Five micromolar hits have been synthesized, and verified within less than 6 weeks, including the measurement of IC50 values.

ULK4, a pseudokinase with some unusual mutations in the kinase catalytic motif, has genetically been linked to some neuropsychiatric disorders like schizophrenia. The first crystal structure of the human ULK4 kinase at high resolution will be discussed here. ULK4 has no apparent phosphotransfer activity but can bind to ATP in a Mg2+ independent manner. A virtual, as well as an experimental, screening was performed to identify small molecule binders of ULK4.

The vaccinia-related kinases 1and 2 (VRK1 and VRK2) were recently associated with poor prognosis, tumor growth and metastasis. The development of chemical probes with appropriate potency and selectivity is a key step to validate their role in cancer and confirm the findings from siRNA or CRISPR/Cas9-based experiments. In this talk, it will be presented the efforts to develop new chemical probes for VRK1 and VRK2 using structure-based drug design approaches.

Small molecules that induce protein degradation through ligase-mediated ubiquitination, have shown considerable promise as a new pharmacological modality. Thalidomide and related IMiDs provided the clinical proof of concept, while significant progress has recently been made towards chemically induced targeted protein degradation using heterobifunctional small molecule ligands. We will present recent work towards a better understanding of the molecular principles that govern neo-substrate recruitment, and other small molecule degraders.

CRELUX, is an integral part of the WuXi AppTec Research Services Division (RSD). We deliver tailored solutions in structure-based drug discovery. By screening our proprietary fragment library using powerful biophysical techniques such as MST, SPR or nanoDSF we successfully support clients already in early stage drug discovery campaigns

New modalities, such as PROTACs, are powerful tools that allow biology assessment of oncogenic targets beyond the conventional kinase inhibition. Focal Adhesion Kinase (FAK) is a key mediator of tumour progression and is overexpressed in many solid tumours; to date, inhibitors targeting FAK kinase activity have shown low success in the clinic. Here, we report the design and characterization of a highly potent FAK degrader with increased efficacy over FAK inhibitor, as well as extended in vivo efficacy.

PROTACs are bifunctional molecules, designed to bind with target protein and E3 ligase to degrade target protein by hijacking cell’s own ubiquitin proteasome system. PROTACs have several advantages but challenges remain in designing optimal PROTACs that has acceptable absorption, distribution, metabolism and excretion (ADME) properties to demonstrate efficacy in vivo. Literature published PROTACs have high MW (beyond rule of 5), low permeability and low oral bioavailability. This presentation will focus on ADME properties of PROTACs with special focus on strategy to improve oral bioavailability.