GSK-3532795/BMS-955176, an inhibitor of HIV-1 maturation was an effective antiviral agent in HIV-1 infected substrates including those with the preexisting polymorphisms that hadn't responded to the first-generation maturation inhibitor (MI) bevirimat. An optimization campaign identified GSK3640254 and VH3739937 (VH-937) as MIs with enhanced antiviral and safety profiles. Both compounds demonstrated efficacy in the clinic, GSK3640254 as a QD oral agent and VH-937 as an agent with potential for infrequent dosing.

Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Ka. I will describe how Relay Therapeutics integrates our Dynamo Platform with DEL screening to identify mutant-selective chemical starting points. From these starting points came the development of RLY-2608, a first-in-class inhibitor demonstrating mutant selectivity in patients.

DNA-encoded libraries enable us to identify thousands of hits from screens using billions of molecules, producing a vast array of potential chemical matter that needs to be triaged efficiently. Here, we show how we leverage the facility of resynthesizing screening hits on-DNA to enable biophysical follow-up. Ultimately, this enables us to make decisions on chemistry resource investments, including synthesis of compounds that may not have been obvious during data analysis.

Identifying small molecule ligands to unprecedented targets is a significant hurdle in drug discovery. DNA-encoded library (DEL) technology is an important component of our Hit ID toolbox. Through a series of case-studies I will discuss lessons learned in the use of DEL to discover hits for emerging targets that represented first-in-class opportunities within our global portfolio.

Protein-detect NMR is widely used in lead discovery campaigns for measuring small molecule interactions with proteins and provides a robust measure of weak affinities. This approach generally requires isotopic labeling. Here, I will discuss an approach for measuring affinities of small molecule ligands to unlabeled proteins that uses a 1D-diffusion filter and ECHOS analysis. This enables protein-detect NMR as a method to characterize ligand-protein interactions for most protein targets.

SPR characterization of interactions between small molecule (SM) therapeutics and membrane proteins is extremely challenging, due to loss of protein activity on the sensing surface and signal interference from detergent micelles. Here, we report SPR characterization of interactions between SMs and an ion channel stabilized in complex with antigen-binding fragments in conditions with low micelle interference, progressing SM therapeutic development of an ion channel target.

I introduce the Higher Throughput Targeted-Chemoproteomic (HiTChem) platform, which harnesses plate-based click chemistry and targeted MS to simultaneously identify multiple therapeutic targets, thereby enabling a more efficient hit-finding process. We will showcase our ongoing efforts using fully functionalized photofragments to identify hits for PARP and multiple bromodomain protein targets in cellular environments, with a higher throughput manner.

RNA plays a ubiquitous role in every facet of the cell life cycle, and its dysregulation frequently underlies various diseases. Arrakis's mission is to solve very broadly the problem of how to drug RNA with small molecules. This presentation covers RNA structure identification, screening, and hit characterization. We utilize an integrative structural biology approach to decipher RNA/ligand interactions and accelerate ligand optimization.

I will highlight how we enabled a structural system for cancer target CDK7 to perform structure-based drug design. I will show examples of liganded complexes with clinical stage compounds in both covalent and non-covalent modalities and discuss how that impacted our drug lead design.

The discovery efforts using our RAPID (Reactive Affinity Probe Interaction Discovery) chemoproteomics platform will be described that led to small molecules that inhibited transporter SLC6A19 and demonstrated in vivo activity in the Pahenu2 model. This work led to the identification of JNT-517, a potential first-in-class clinical candidate for the treatment of phenylketonuria which has demonstrated positive POC in a Ph1b clinical trial.

Our NCATS team and Regulonix developed NaV1.7 channel regulators by targeting CRMP2 sumoylation, which s an allosteric regulator of the channel. Regulonix discovered that surface expression of the channels can be decreased due to loss of CRMP2 sumoylation. Through virtual screening and hit search, lead compound AZ194 was discovered. The NCATS team expanded the library of inhibitors from AZ194 to more than 450 analogs, with novel structures, improved potency, and ADME properties.

Triggering receptor expressed in myeloid cells 2 (TREM2) is a lipid-sensing receptor that promotes the growth, migration, and anti-inflammatory effects of microglia that are upregulated within pathological microenvironments. Loss-of-function TREM2 variants impose genetic risk for Alzheimer’s disease (AD). Herein we highlight the activity and profile of Vigil’s first-in-class small molecule TREM2 agonists for treatment of neurodegenerative diseases.