G2Retro as a two-step graph generative models for retrosynthesis prediction.

Retrosynthesis is a procedure where a target molecule is transformed into potential reactants and thus the synthesis routes can be identified. Recently, computational approaches have been developed to accelerate the design of synthesis routes. In this paper,we develop a generative framework G2Retro for one-step retrosynthesis prediction. G2Retro imitates the reversed logic of synthetic reactions. It first predicts the reaction centers in the target molecules (products), identifies the synthons needed to assemble the products, and transforms these synthons into reactants. G2Retro defines a comprehensive set of reaction center types, and learns from the molecular graphs of the products to predict potential reaction centers. To complete synthons into reactants, G2Retro considers all the involved synthon structures and the product structures to identify the optimal completion paths, and accordingly attaches small substructures sequentially to the synthons. Here we show that G2Retro is able to better predict the reactants for given products in the benchmark dataset than the state-of-the-art methods.

Examination of the Impact of Triazole Position within Linkers on Solubility and Lipophilicity of a CDK9 Degrader Series.

Optimization of degrader properties is often a challenge due to their beyond-rule-of-5 nature. Given the paucity of known E3 ligases and the often-limited choice of ligands with varied chemical structures for a given protein target, degrader linkers represent the best position within the chimeric molecules to modify their overall physicochemical properties. In this work, a series of AT7519-based CDK9 degraders was assembled using click chemistry, facilitating the tuning of aqueous solubility and lipophilicity while retaining their linker type and molecular weight. Using chromatographic logD and kinetic solubility experiments, we show that degraders with similar chemical constitution but varied position of the embedded triazole demonstrate different lipophilicity and aqueous solubility properties. Overall, this work highlights the impact of triazole placement on linker composition through application of click chemistry for degrader synthesis and its ability to be used to promote the achievement of favorable physicochemical properties.

Bifunctional degraders of cyclin dependent kinase 9 (CDK9): Probing the relationship between linker length, properties, and selective protein degradation.

Cyclin-dependent kinase 9 (CDK9) is a promising therapeutic target in multiple cancer types, including acute myeloid leukemia (AML). Protein degraders, also known as proteolysis targeting chimeras (PROTACs), have emerged as tools for the selective degradation of cancer targets, including CDK9, complementing the activity of traditional small-molecule inhibitors. These compounds typically incorporate previously reported inhibitors and a known E3 ligase ligand to induce ubiquitination and subsequent degradation of the target protein. Although many protein degraders have been reported in the literature, the properties of the linker necessary for efficient degradation still require special attention. In this study, a series of protein degraders was developed, employing the clinically tested CDK inhibitor AT7519. The purpose of this study was to examine the effect that linker composition, specifically chain length, would have on potency. In addition to establishing a baseline of activity for various linker compositions, two distinct homologous series, a fully alkyl series and an amide-containing series, were prepared, demonstrating the dependence of degrader potency in these series on linker length and the correlation with predicted physicochemical properties.