GSK3640254 is an HIV-1 maturation inhibitor (MI) with antiviral activity towards a wide range of clinically-relevant polymorphic variants, which has demonstrated efficacy in HIV-1 infected patients in Phase IIb clinical trials. In contrast to classical HIV-1 protease inhibitors that act by binding to the viral protease, GSK3640254 binds to the viral Gal-polyprotein, preventing its final processing by the HIV-1 protease and resulting in the release of an immature, non-infectious virus.

We employed a combined computational and crystallographic fragment screening approach to identify novel binding sites in the anticancer target tubulin. Based on our study and using straightforward chemistry, we fully rationally designed a small molecule antitubulin inhibitor for the first time, which exhibits a unique molecular mechanism of action. We further exploited the conformational switch properties of a designed tubulin ligand to assess its unbinding using time-resolved femtosecond serial crystallography.

The TEAD family of transcription factors are implicated in cancer but developing a central pocket assay posed a hurdle toward fully understanding inhibition. We have overcome the challenges of TEADs central lipid pocket and developed a robust biochemical assay, using structural elucidation and computational chemistry to understand the MOAs for small molecule inhibitors. We provide hypotheses of different MOAs which could contribute to development of more potent and selective inhibitors.

I describe the discovery of the in vivo active KRASG12C inhibitor BI-0474. We identified small molecules that bind reversibly to the Switch II pocket on KRAS. These binders were optimized by growing toward Cys12 and then attaching the Michael acceptor warhead to react with Cys12. Our approach offers an alternative to discover KRASG12C inhibitors and provides a starting point for the discovery of inhibitors against other oncogenic KRAS mutants.

A successful fragment screening campaign against KEAP1 provided key starting points and information to generate a highly potent series against this PPI. To develop a second potent series, the key pharmacophoric elements were used to search the GSK collection. An SBDD campaign on the resulting hits generated a second potent series suitable for lead optimisation.

Transcription factors (TFs) make for compelling drug targets but have been historically hard to drug. Various TFs work with the BAF remodeling complex to open specific regions of chromatin. Using SPI1 as an example, we will highlight how Foghorn has developed a drug discovery platform to identify and target TF-BAF protein-protein interactions responsible for driving disease.

Helically constrained (Helicon) peptides are a drug modality that allows the targeting of undruggable protein-protein interactions in cells. We have developed tandem platforms that enable the de novo discovery of helical hits to targets without any prior knowledge of their helix-binding properties, and that enable the rapid optimization of these hits to molecules with drug-like properties via the multiplexed synthesis and screening of thousands of peptides per week.

Selectivity is a key consideration in medicinal chemistry campaigns. When a target has high sequence similarity with off-target proteins, selectivity may be challenging. Where smaller selectivity margins are sufficient, high-quality measurements are key to reliable detection. The long residence time of tight complexes can lead to unfavorably long incubation times in many biochemical/biophysical assays leading to inaccurate measurements. Kinetic measurements (SPR) have the advantage of measuring affinities pre-steady state with high accuracy. The “chaser” SPR method allows accurate measurements of very slow dissociation constants, extending the range of measurable affinities with the high accuracy needed for reliable selectivity margins.

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

RAPID is a next-generation chemoproteomics technology for discovering small molecules that bind to any target of interest inside of a living cell. Using RAPID, we have discovered the first-described ligands for the transcription factor IRF3, which drives the interferon response downstream of STING.

Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Using structural and biochemical insights, we developed drug screening strategies and identified the first mitofusin activators and inhibitors that directly increase or inhibit mitofusin activity by modulating mitofusin conformations and oligomerization. Characterization of mitofusin modulators in modulating mitochondrial fusion, function, and signaling and their pharmacological potential in diseases will be discussed.

We describe first rational targeting of a specific histidine residue in a protein binding site using sulfonyl exchange chemistry. Using structure-based drug design we incorporated sulfonyl fluoride and triazole reactive group into cereblon binders resulting in potent covalent inhibitors and molecular glues through engagement of His353. Chemical probes and covalent labeling strategy described here will broadly impact this exciting area of therapeutic research.

Normalization of axonal microtubules (MTs) dynamics is a promising strategy to treat neurodegenerative tauopathies, including Alzheimer's disease. Central to this strategy, however, is the identification of MT-stabilizing compounds that could reach effective brain concentrations and doses that would not be systemically toxic. The presentation will provide an overview of structure-activity relationship efforts that led to the identification of selected members of the 1,2,4-triazolo[1,5-a]pyrimidine class as candidates for further development.