Metallo-ß-lactamases, such as NDM-1, VIM-1, and IMP-1 possess poor homology in their active sites.  Despite their poor homology, a class of compounds having a biphenyl tetrazole (BPT) core – identified earlier as a B. fragilis metallo-beta-lactamase inhibitor with weak inhibitory activity against NDM-1 in a biochemical assay – was evolved into pan inhibitor first then into multiple clinical candidates.

Here we report the discovery of two lead series from five fragment hits for our PRMT5/MTA program. The hits were identified via an SPR fragment screen followed by X-ray crystallography. We will outline a two-phase process encompassing fragment optimization followed by fragment growing strategies. Access to versatile synthetic intermediates, synthetic traceability, and enablement of structure-based drug design were important success factors. Further optimization of potency, selectivity, and pharmacokinetic parameters resulted in the discovery of MRTX1719. MRTX1719 is currently in a Phase 1/2 clinical study in solid tumors with MTAP-deletion.  

Aggregation of the tau, an intrinsically disordered protein (IDP), into neurofibrillary tangles is one of the hallmarks of Alzheimer’s disease (AD). In this presentation, we discuss a fragment-based approach, employing protein NMR, to discover tau binders that could potentially disrupt tau aggregation. Chemical elaboration of fragment hits, driven by both NMR and surface plasmon resonance (SPR), resulted in tau binders with affinities in the low double-digit micromolar range.

Renin is an aspartic protease enzyme and the development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. Based on initial BACE1 inhibitors, a repertoire iminopyrimidinones is a novel pharmacophore for aspartyl protease inhibition. In this presentation, we describe how we leverage structural information from the database and modified substitution around this pharmacophore to develop a potent, selective, and orally active renin inhibitor.

The discovery/development of new drugs is a highly costly and slow process while repositioning old drugs to treat other diseases is increasingly becoming an attractive proposition. In this context, at the interface between drug design and drug repositioning, we decided to apply our integrative multidisciplinary drug design approach, DOTS, to deconstruct and optimize an existing drug in a Structure-Based ‘Hit-to-Lead’ optimization approach on a newly validated target. In the present study, we designed a ‘derivative’ library of the deconstructed drug by gradually implementing key chemical modifications in an automated process to increase protein-ligand interactions and activity toward the new target.

An overview of reactive cysteines in neuroscience focused research will be discussed. Approaches for covalent fragment screening and drug discovery applications will also be covered.

Drug discovery approaches aimed at designing targeted covalent inhibitors are currently heavily pursued by academia, biotech, and pharmaceutical companies. These approaches have culminated in the recent approval of several Cys-covalent drugs in oncology. With the resurgence and the success of such covalent drugs, our studies focus on the identification of novel and effective design strategies that widen the available target space beyond cysteine, to include other more abundant residues such as lysine, tyrosine, or histidine. I will report on fragment- and structure-based strategies that include the design of potent and selective Lys- and His-covalent agents targeting oncogenic proteins.

The polar chemistry of activity-based protein profiling (ABPP) probes was reversed by deploying the nucleophilic hydrazine pharmacophore found in old CNS drugs to show organohydrazines are active-site directed and mechanism-based inhibitors of protein classes that are difficult to drug. Using the first N-nucleophile fragment/probe library, we showed that potent and selective inhibitors can be developed and that reverse-polarity ABPP can advance small molecules that modulate diverse electrophile-dependent functions.

The discovery of a targetable cryptic pocket in KrasG12C has ignited interest in covalent targeting and, in particular, fragment-based screening approaches to identify covalent ligands for difficult-to-drug targets. I will introduce a novel screening method that aims to streamline the covalent drug discovery process by simultaneously providing binding site information.

FBDD has proven to be a successful method for many drug targets. The current state-of-the-art in fragment optimization is structure-based drug design, and it is therefore recommended to have a path to 3D structural information. Here we present such a path while targeting KRAS, using solely NMR spectroscopy. This talk aims to present the current possibilities in NMR spectroscopy when starting a fragment-based drug design discovery campaign. We will therefore present an NMR pipeline from fragment screening to 3D structure, targeting the protein KRAS. We will also present our latest NMR developments for structure-based drug design by NMR.

TEADs transcription factors bind to co-activators YAP1 or TAZ to promote tumor growth and metastasis. We report isoindoline and octahydroisoindole small molecules with a cyanamide electrophile that form a covalent complex with a cysteine in the TEAD palmitate cavity. Compounds inhibited YAP1 binding to TEADs and cocrystal structures revealed their binding mode. Compounds inhibited TEAD1-4 transcriptional activity in mammalian cells. Several compounds inhibited cell viability in several cancer cell lines.