Pharmacological activation of the innate immune receptor STING is a promising therapeutic strategy for cancer. MSA-2 is an orally available non-nucleotide human STING agonist. Extensive experimental analysis showed that MSA-2 exists as interconverting monomers and dimers in solution, but only dimers bind and activate STING. Extracellular acidification, mimicking the tumor microenvironment, increased MSA-2 cellular potency. These properties appear to underpin the favorable activity and tolerability profiles of systemically administered MSA-2.

I will show how we were able to design a new STING agonist that overcame the systemic delivery issues plaguing 1st generation agonists such as poor metabolic stability and poor physio-chemical properties. SNX281 is potent, specific, and active against all human isoforms of STING and rapidly activates downstream signaling and induces type I IFN. Our compound entered Phase1 clinical trials in November 2020.

Selinexor, a covalent XPO1 inhibitor, is approved in the U.S. in combination with dexamethasone for penta-refractory multiple myeloma. In this talk we will describe clickable probes based on XPO1 inhibitors selinexor and eltanexor for the labeling of XPO1 in live cells to assess target engagement and selectivity. We use mass spectrometry-based chemoproteomic workflows to profile the proteome-wide selectivity of selinexor and eltanexor and show that they are selective for XPO1.

• Virtual reality provides a novel interface for collaboration, integration of computational workflows, and enhances visual exploration of drug interactions
• Nanome has partnered with E4C to combat SARS-CoV-2 through identifying novel binding pockets of NSP12
• InSilico Medicine used Nanome to curate AI-generated molecules targeting SARS-CoV-2 NSP5a

As the pandemic was breaking, Diamond and the Weizmann Institute performed a huge crystallographic and electrophile fragment screen on Mpro of SARS-CoV-2. Data were released into the public domain and announced on Twitter, triggering a large international response that led to a fully open crowd-sourcing effort, to bring a safe, simple, oral antiviral to patients in time for this pandemic. This will be an update and prospective on the project.

In a search for drugs against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries with almost 6000 compounds against the SARS-CoV-2 main protease (M^pro), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. We identified 37 compounds binding to M^pro. In subsequent cell-based assays, five compounds showed antiviral activity at non-toxic concentrations. Additionally, we identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.

We will present how NMR can contribute to the global effort against the COVID-19 pandemic. In a second part, I will briefly present preliminary results on new methodologies for studying small-molecule protein complexes.

We used two machine learning engines to predict drug repurposing candidates for the treatment of COVID-19. A graph convolutional network using host-virus interactome data revealed potential host-antiviral targets that enabled PolypharmDB, a database of small molecule drugs and their predicted polypharmacology, to be queried for relevant putative modulators. Several of the predicted agents demonstrated antiviral activity in cell-based assays, with the oncology drug, capmatinib, demonstrating broad spectrum antiviral activity against several coronaviruses, including SARS-CoV-2.

Through a massive crystallographic screening and computational docking effort we identified new chemical matter primarily targeting the active site of the macrodomain of the non-structural protein 3 (Nsp3) of SARS-CoV-2. This enzyme is a promising antiviral target because catalytic mutations render viruses non-pathogenic.

Using structural similarity screening and biophysical methods, we identified that Eltrombopag, an FDA-approved drug, is a direct inhibitor of pro-apoptotic BAX. Eltrombopag binds the BAX activation site distinctly from BAX activators, preventing them from triggering BAX conformational transformation and simultaneously promoting stabilization of the inactive BAX structure. Our data demonstrate insights into a mechanism of BAX inhibition and suggest a potential use for Eltrombopag in diseases of uncontrolled cell death.

We developed a method that endows small molecules with the ability to recruit and activate CAR Ts to kill tumor cells. It is based on a CAR T with a generic and inert scFv that gets switched on by a catalytic Fab programmed with small molecules targeting tumor cells. In proof-of-concept studies, this switchable CAR T system mediated potent and specific eradication of cancer cells in vitro and in vivo.

Stable cell lines are critical tools of cellular assays in drug discovery and development.  Over-expressing cell lines are needed to screen for hits, while functional cell lines are needed for "lead" identification. In the past couple of decades, GenScript has developed 200+ stable cell line products expressing the most popular drug targets including GPCR, FcR, immune checkpoints, and COVID19 related proteins to accelerate your drug discovery and clinical translation.