An affinity-based screen of 10^13 macrocyclic peptides identified PCSK9 ligands with high affinity and partial disruption of LDLR binding. The structure of the peptides in complex with PCSK9 revealed a novel, induced-fit pocket, as well as insights into key binding contacts and opportunities to enhance disruptor function. Structure-based design led to macrocyclic peptides with enhanced function, pharmacokinetic properties, and pharmacologic inhibition of PCSK9 in mice.

The importance of cysteinyl leukotrines as mediators in airway inflammation and bronchoconstriction motivated development of cysteinyl-leukotriene-C4 synthase inhibitors aimed as differentiated treatment for patients with asthma.An initial hit was identified in a focused screen of 400 commercially available compounds but suffered from poor physicochemical properties and lack of cellular activity. Rational design, underpinned by key structural information, resulted in a moderately metabolically stable lead series. Further extensive optimization focusing heavily on reducing off-target interactions eventually delivered the clinical candidate AZD9898.

X-Chem is a leader in providing cutting edge technology solutions to drug hunters. Rooted in DEL technology, X-Chem's expertise extends across multiple target classes and therapeutic modalities, including protein-protein interactions, epigenetic targets, covalent inhibitors, protein degraders, GPCRs and many others. In this presentation we will describe X-Chem's expanded capabilities, our approach to DEL design, and share illustrative examples.

In the last 3 years, drug discovery was revolutionized by the development of ultra-large libraries of REadily AccessibLe (REAL) compounds. This talk will describe V-SYNTHES as a new iterative approach for fast structure-based virtual ligand screening of billions of REAL compounds. Recently validated with 11 billion compound library in a prospective discovery of new antagonist chemotypes for Cannabinoid receptors and other key targets, V-SYNTHES effectively scales to >10¹⁵ compounds.

An HTS was conducted using a FRET-based assay measuring poly-auto-Ubiquitination of Parkin to identify SM activators. We identified PAMs from several series and successfully enhanced potency and improved drug-like properties. While the compounds act as Parkin PAMs they failed to enhance the Parkin translocation rate to mitochondria or to enact mitophagy in cell-based assays. In the context of the cellular milieu, the therapeutic opportunity to activate Parkin is very narrow. The authors of our unpublished work include Evgeny Shlevkov, Param Murugan, Dan Montagna, Eric Stephan, Addy Hadzipasic, James Harvey, Rajesh Kumar, Sonya Entova, Nupur Bansal, Shari Bickford, LaiYee Wong, Warren Hirst, Andreas Weihofen, and Laura Silvian, Biogen.

Several chemical genetic approaches have emerged that enable rapid and acute control of target protein homeostasis. These technologies have elevated the understanding of target biology in both in vitro and in vivo settings exemplifying the power of rapid target protein modulation. We developed two non-overlapping aTAG systems providing flexibility in choice of aTAG properties and the opportunity to multiplex aTAG systems within the same context to further explore complex biology.

Conformation-specific antibodies represent a powerful tool for drug discovery. These tools are capable of binding to a target of interest and trapping the target in a specific conformation. We have extended their application to include lead finding for difficult-to-drug targets. Specifically, the application of conformation-specific antibodies to fragment-based lead discovery (FBLD) using surface plasmon resonance (SPR) on a high value therapeutic target will be described. A conformation-specific antibody was successfully used to lock the target in the desired conformational state leading to the discovery of fragment hits that were previously undetectable in the absence of the antibody.

I will present on my paper which was recently published in JACS, about the the use of machine learning to design cyclic peptide inhibitors.

I will present applications of nanobodies in cryo EM (Megabodies). We have used megabodies to study human ion channels in order to facilitate drug discovery efforts. 

DNA-encoded libraries enable the screening of billions of small molecules at a depth of chemical space not available with other affinity screening methods and small molecule libraries. The analysis of data is more complex, however, requiring specialized visualizations to view potential SAR and off-DNA synthesis of the small molecule warhead to confirm binding. In this presentation, we will review the discovery of two clinical candidates from ELT screens, one an inhibitor of soluble epoxide hydrolase (sEH) and the other an inhibitor of receptor-interacting serine/threonine-protein kinase 1 (RIPK1).

Our studies in the structural modification of peptide molecules have resulted in several novel cyclization processes. A particularly intriguing aspect of our recent work deals with the development of new methods for backbone peptide modification. The corresponding reactions have resulted in new macrocyclic architectures and have paved a way to understanding the effect of structural rearrangements on the behaviour of macrocycles. These and related topics will be discussed.

Collaborative Drug Discovery (CDD) provides a whole solution for today’s biological and chemical data needs, differentiated by ease-of-use and superior collaborative capabilities. CDD Vault® software includes Activity & Registration, Visualization, Inventory, and ELN capabilities. Researchers can archive, mine, and securely collaborate within CDD Vault. Collaborative hypothesis generation and evaluation allow multiple perspectives for multi-parameter optimization.

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.

Proteros offers identification of qualified hits for challenging targets with innovative inhibition modes. Jump start your discovery projects by tapping Proteros´ renowned excellence in protein science, biochemistry/biophysics, protein X-ray crystallography and cryo-electron microscopy as well as HTS of Proteros´ hand selected fragment and small molecule libraries. In a case study we demonstrate the identification of pocket specific fragments and their evolution from hits to nM and long residence time inhibitors.

We have adapted and applied IR-MALDESI-MS, a novel label-free tool, for high throughput (< 1sample/sec) biochemical and cellular assays. MALDESI-MS allows direct ambient analysis of complex reaction mixtures in common biochemical buffers and cellular medias without sample clean-up. Examples of both cellular and biochemical assays will be given along with other potential applications within the lead discovery space.