Discovering novel kinase modulators that combine high selectivity with the ability to regulate noncatalytic functions remains a crucial goal in kinase drug discovery. Here, we use Aurora A as a case study to demonstrate that proteolysis-targeting chimeras (PROTACs) provide a compelling solution to these challenges. We discovered M9101, a potent, selective and in vivo active Aurora A PROTAC degrader, developed from a promiscuous kinase inhibitor warhead. M9101 potently degrades Aurora A with a DC50 value of 2.3 nM in MD-MBA-231 cells and demonstrates exceptional selectivity in a global proteomic analysis. Furthermore, M9101 effectively depletes Aurora A in vivo. This study presents a valuable chemical tool for probing the noncatalytic biology of the kinase and, importantly, highlights that selective kinase degraders are achievable even from promiscuous binding ligands.

Cyclobutane amino nitriles (CBANs), as a class of sterically hindered alpha,alpha-disubstituted unnatural amino acid derivatives, have garnered notable interest in pharmaceutical research due to their capacity to enhance molecule potency, metabolic stability and selectivity. However, the advancement and exploration of the chemical space of CBANs are impeded by general synthetic strategies, particularly for sterically more hindered vicinal tetrasubstituted derivatives. Here we report the diastereoselective synthesis of congested CBANs using commercially available ketones or aldehydes through a modular and precise process. The key to this transformation involves harnessing the unique reactivity of triplet nitrene. This enables a diradical-mediated ring expansion of alkylidenecyclopropanes and is combined with a titanium(IV)-catalysed cyanylation step. The reaction, which is supported by experimental and computational mechanistic studies, readily delivers hindered vicinal mono- and di-substituted CBANs, along with spiro-fused architectures, showcasing substantial structural diversity. High functional-group compatibility, including with groups that are incompatible with traditional multi-step processes and are medicinally relevant, is also observed.

Though zinc-iodine (Zn-I2) batteries hold considerable promise for grid-scale energy storage, their development remains constrained by zinc dendrite formation, detrimental side reactions, and polyiodide shuttle. In this work, sodium camphorsulfonate (SCS) is introduced as a biomimetic bidirectional electrolyte additive to simultaneously address these issues. At the anode, SCS participates in the Zn2 + solvation to suppress HER, while its preferential adsorption on Zn anode guides the dendritefree (002) plane. At the cathode, the SCS exhibits strong binding affinity toward I2, effectively inhibiting polyiodide shuttle. Moreover, the adsorbed SCS layer on Zn acts as a barrier against migrating polyiodides, mitigating Zn anode interfacial corrosion. Thus, the Zn||Zn symmetric cell with 10 SCS/BE demonstrates ultra-stable cycling for 1449 h at 5 mA cm- 2/5 mAh cm- 2. The Zn-I2 full cell retains 154.0 mAh g- 1 capacity after 26 000 cycles at 5 A g- 1. The corresponding pouch battery with a 20 & micro;m Zn foil and a high iodide loading (10.5 mg cm- 2) cathode displays a capacity of 175.1 mAh g- 1 after 500 cycles at 0.5 A g- 1. This work provides a cost-effective design strategy for stabilizing both electrodes in Zn-I2 batteries through a single molecular additive and guarantee a durable cyclic performance of Zn-I2 batteries.

Background: Alterations in the amine submetabolome are closely associated with cellular metabolic status and are important for understanding metabolic regulation under intervention conditions. In this study, a stable isotope labeling derivatization combined with liquid chromatography-mass spectrometry (LC-MS) was employed to characterize alterations in the cellular amine submetabolome. Optimization of chromatographic separation and cellular metabolic quenching procedures improved the separation performance of amine metabolites while enabling more accurate preservation of the metabolic state at the time of sampling. Results: The established method was applied to a D-lactate treated BEAS-2B cell model to evaluate amine submetabolome alterations under different compound intervention conditions. The results demonstrated that selenomethionine (SeMet) and berberine alleviated D-lactate induced abnormalities in the amine submetabolome and showed metabolic regulatory effects consistent with tumor-suppressive trends observed under in vivo experiments. Significance: Overall, this analytical strategy enables characterization of the amine submetabolome in complex biological samples and provides a reliable methodological reference for metabolome-based investigations of cellular metabolic alterations.

Halogenation has been used as a useful strategy to optimize an imidazolium-based macrocyclic ultralong-acting neuromuscular blocking agent for improved bioactivity and biocompatibility. A structure-activity relationship study for 18 compounds reveals that monofluorinated macrocycle IMC-X5 displays blockade profiles generally superior to those of lead compound IMC-0. In vivo tests with a rat model show that, compared with those of IMC-0, the onset, profound blockade, and moderate blockade-to-spontaneous respiration times of IMC-X5 at the same dose of 0.2 mg/kg shortens by 47%, extends by 34%, and shortens by 89%, respectively, while the onset activity surpasses that of cisatracurium, one of the main neuromuscular blocking agents, of a clinically associated dose. Moreover, the profound blockade of IMC-X5 can be rapidly reversed by a biocompatible acyclic cucurbit[n]uril (ACB) antagonist at any stage of blockade. IMC-X5 also exhibits a biosafety superior to that of IMC-0. The two agents thus form a promising partnership featuring ultralong-acting blockade and on-demand reversal.

The substitution of classical dienes with C-C bonds in Diels-Alder-type reactions is a compelling paradigm in modern syntheses. Although activation of C-C bonds alpha to a single heteroatom has been well established, extending this strategy to synthetically valuable C-C moieties alpha to two heteroatoms remains challenging because of the competing activation of adjacent C-heteroatom bonds. Here we overcome this limitation through the development of a selective C2-C3 bond activation protocol in beta-lactams, which operates with remarkable fidelity despite the presence of the intrinsically more reactive N1-C2 bond. Key to this work is the phosphine oxide-ligating Ni-Al bimetallic catalyst system, which positions nickel at C2-C3, suppresses C-N activation and facilitates annulation with diverse pi-systems (alkynes/alkenes). This mechanistically guided strategy affords delta-lactam homologues in up to 99% yield, representing a marked departure from conventional cycloaddition approaches constrained by inherent bond reactivity hierarchies.

Mutations within the transmembrane domains (TMDs) of single-pass transmembrane receptors often cause aberrant, ligand-independent receptor signaling associated with diverse malignancies, but their mechanism of action remains largely unknown. These TMD mutations are generally not targetable as they are buried in the membrane. Here, we determined the mechanism of a gain-of-function (GOF) TMD mutation of interleukin-7 receptor (IL-7R) associated with T cell acute lymphoblastic leukemia and addressed the possibility of directly targeting the TMD mutation by using rationally designed transmembrane helices to restore order to uncontrolled signaling. We find that the GOF mutation of IL-7R severely shifts the TMD homodimerization interface, causing the receptor to homodimerize in a geometry that activates downstream signaling independent of ligand. Designed transmembrane helices that interfere with the new interface, delivered with mRNA technology, selectively block ligand-independent but not ligand-dependent signaling. Our study provides a conceptual framework for understanding and repairing disease-causing TMD mutations of single-pass cytokine receptors.