Computational Mapping of Dirhodium(II) Catalysts.

The chemistry of dirhodium(II) catalysts is highly diverse, and can enable the synthesis of many different molecular classes. A tool to aid in catalyst selection, independent of mechanism and reactivity, would therefore be highly desirable. Here, we describe the development of a database for dirhodium(II) catalysts that is based on the principal component analysis of DFT-calculated parameters capturing their steric and electronic properties. This database maps the relevant catalyst space, and may facilitate exploration of the reactivity landscape for any process catalysed by dirhodium(II) complexes. We have shown that one of the principal components of these catalysts correlates with the outcome (e.g. yield, selectivity) of a transformation used in a molecular discovery project. Furthermore, we envisage that this approach will assist the selection of more effective catalyst screening sets, and, hence, the data-led optimisation of a wide range of rhodium-catalysed transformations.

Activity-Directed Synthesis of Inhibitors of the p53/hDM2 Protein-Protein Interaction.

Protein-protein interactions (PPIs) provide a rich source of potential targets for drug discovery and biomedical science research. However, the identification of structural-diverse starting points for discovery of PPI inhibitors remains a significant challenge. Activity-directed synthesis (ADS), a function-driven discovery approach, was harnessed in the discovery of the p53/hDM2 PPI. Over two rounds of ADS, 346 microscale reactions were performed, with prioritisation on the basis of the activity of the resulting product mixtures. Four distinct and novel series of PPI inhibitors were discovered that, through biophysical characterisation, were shown to have promising ligand efficiencies. It was thus shown that ADS can facilitate ligand discovery for a target that does not have a defined small-molecule binding site, and can provide distinctive starting points for the discovery of PPI inhibitors.

Light-mediated multi-target protein degradation using arylazopyrazole photoswitchable PROTACs (AP-PROTACs).

Light-activable spatiotemporal control of PROTAC-induced protein degradation was achieved with novel arylazopyrazole photoswitchable PROTACs (AP-PROTACs). The use of a promiscuous kinase inhibitor in the design enables this unique photoswitchable PROTAC to selectively degrade four protein kinases together with on/off optical control using different wavelengths of light.

Facts, Patterns, and Principles in Drug Discovery: Appraising the Rule of 5 with Measured Physicochemical Data.

The rule of 5 was designed to estimate the likelihood of poor absorption or permeation, noting the impact of poor solubility. This Perspective explores the impact of various physicochemical descriptors and contemporary lipophilicity measurements on permeability and solubility, showing that the distribution coefficient log D7.4 (rather than log P) is the most impactful parameter. Molecular weight, almost invariably the defining characteristic of "beyond the rule of 5" compounds, has little impact on solubility when log D7.4 measurements and aromaticity are considered. Predicting permeation is more complex, given passive and carrier transport mechanisms; however, notable patterns of behavior are apparent, giving insight even "beyond the rule of 5". Recommended best practices should involve using the facts (measurements) and the patterns they reveal to establish informative principles rather than fastidious rules.

Structural Insights into PROTAC-Mediated Degradation of Bcl-xL.

The Bcl-2 family of proteins, such as Bcl-xL and Bcl-2, play key roles in cancer cell survival. Structural studies of Bcl-xL formed the foundation for the development of the first Bcl-2 family inhibitors and FDA approved drugs. Recently, Proteolysis Targeting Chimeras (PROTACs) that degrade Bcl-xL have been proposed as a therapeutic modality with the potential to enhance potency and reduce toxicity versus antagonists. However, no ternary complex structures of Bcl-xL with a PROTAC and an E3 ligase have been successfully determined to guide this approach. Herein, we report the design, characterization, and X-ray structure of a VHL E3 ligase-recruiting Bcl-xL PROTAC degrader. The 1.9 Å heterotetrameric structure, composed of (ElonginB:ElonginC:VHL):PROTAC:Bcl-xL, reveals an extensive network of neo-interactions, between the E3 ligase and the target protein, and between noncognate parts of the PROTAC and partner proteins. This work illustrates the challenges associated with the rational design of bifunctional molecules where interactions involve composite interfaces.

Targeting the Regulatory Site of ER Aminopeptidase 1 Leads to the Discovery of a Natural Product Modulator of Antigen Presentation.

ER aminopeptidase 1 (ERAP1) is an intracellular enzyme that generates antigenic peptides and is an emerging target for cancer immunotherapy and the control of autoimmunity. ERAP1 inhibitors described previously target the active site and are limited in selectivity, minimizing their clinical potential. To address this, we targeted the regulatory site of ERAP1 using a high-throughput screen and discovered a small molecule hit that is highly selective for ERAP1. (4aR,5S,6R,8S,8aR)-5-(2-(Furan-3-yl)ethyl)-8-hydroxy-5,6,8a-trimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid is a natural product found in Dodonaea viscosa that constitutes a submicromolar, highly selective, and cell-active modulator of ERAP1. Although the compound activates hydrolysis of small model substrates, it is a competitive inhibitor for physiologically relevant longer peptides. Crystallographic analysis confirmed that the compound targets the regulatory site of the enzyme that normally binds the C-terminus of the peptide substrate. Our findings constitute a novel starting point for the development of selective ERAP1 modulators that have potential for further clinical development.

PROTAC-Mediated Degradation of Bruton's Tyrosine Kinase Is Inhibited by Covalent Binding.

The impact of covalent binding on PROTAC-mediated degradation of BTK was investigated through the preparation of both covalent binding and reversible binding PROTACs derived from the covalent BTK inhibitor ibrutinib. It was determined that a covalent binding PROTAC inhibited BTK degradation despite evidence of target engagement, while BTK degradation was observed with a reversible binding PROTAC. These observations were consistently found when PROTACs that were able to recruit either IAP or cereblon E3 ligases were employed. Proteomics analysis determined that the use of a covalently bound PROTAC did not result in the degradation of covalently bound targets, while degradation was observed for some reversibly bound targets. This observation highlights the importance of catalysis for successful PROTAC-mediated degradation and highlights a potential caveat for the use of covalent target binders in PROTAC design.