Cell Chemical Biology

RAGE-mediated activation of the formin DIAPH1 and human macrophage inflammation are inhibited by a small molecule antagonist Theophall et al. identify a therapeutic approach for modifying disease progression in diabetes. They describe an antagonist targeting RAGE, which inhibits the RAGE-DIAPH1 interaction, accelerating wound healing in type 2 diabetic mice and reducing inflammation in peripheral blood mononuclear cell–derived macrophages from patients with type 1 diabetes.

Online now! RAGE-mediated activation of the formin DIAPH1 and human macrophage inflammation are inhibited by a small molecule antagonist #chembiol

Inter- and intra-tumoral ALDH1 heterogeneity in breast cancer identifies therapeutic opportunities for ALDH1A-specific inhibitors Pequerul et al. map inter- and intratumoral ALDH1 isoform heterogeneity in breast cancer linking ALDH1A3 and ALDH1A2 expression to poor prognosis in high-grade tumors. Integrating profiling, functional assays, and inhibitors, they identify contexts where ALDH1A-selective inhibition may be advantageous, supporting isoform-specific ALDH-targeted strategies.

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Valence and avidity determine the agonistic activity of anti-TNFR2 nanobody fusion proteins TNFR2 agonists are attracting translational interest for the treatment of autoimmune diseases. Anany et al. analyzed various TNFR2-targeting nanobody constructs and identified avidity and valence as crucial factors for agonistic activity. The nanobody TNFR2 agonists reached and even surpassed the NF-κB stimulating activity of TNF- and antibody-based agonist benchmarks.

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Sensing within: Mitochondrial inside-out signal transduction Sainz and Oflaz et al. describe mitochondrial inside-out signaling (mitochondria-initiated signaling mechanisms), provide mechanistic insights into this distinct and underappreciated signaling modality, and discuss how these signaling events influence cellular health with a focus on their implications for neuronal physiology and disease.

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A base editor facilitates simultaneous purine and pyrimidine substitutions for ex vivo and in vivo mutagenesis screens http://dlvr.it/TN9vP8

Pharmacologic interrogation of USP28 cellular function in p53 signaling http://dlvr.it/TN9tBM

A covalent inhibitor targeting Cys16 on RhoA in colorectal cancer http://dlvr.it/TN9rgP

Structural basis of adenosine 2A receptor-balanced signaling activation relies on allosterically mediated structural dynamics http://dlvr.it/TN9qTx

A potent NLRP3 inhibitor effective against both MCC950-sensitive and -resistant inflammation http://dlvr.it/TN9p5R

BLOC-1 and BORC: Complex regulators of endolysosomal dynamics http://dlvr.it/TN9mpn

Disruption to the gut microbiome by non-antibiotics is linked to infection risk http://dlvr.it/TN9lNG

tRNA-derived RNA promotes autophagy for kidney protection http://dlvr.it/TN9jxt

Sweet signaling for ferroptosis http://dlvr.it/TN9h9s

Activation primes GPCRs for versatile coupling http://dlvr.it/TN9fWv

Meet the authors: Raffaella De Pace, Chad Williamson, and Juan Bonifacino http://dlvr.it/TN9cVw

Meet the authors: Canyong Guo and Kurt Wüthrich http://dlvr.it/TN9Zvp

The September issue of Cell Chemical Biology is live! Click here to read more: http://dlvr.it/TN9Yd1

A potent NLRP3 inhibitor effective against both MCC950-sensitive and -resistant inflammation Targeting dysregulated inflammasome activity is critical in treating inflammatory disease. Kim et al. identify ZAP-180013 as a selective NLRP3 inhibitor that disrupts inflammasome assembly and overcomes MCC950 resistance. The compound demonstrates efficacy in both local and systemic inflammation models, highlighting its translational therapeutic potential.

Online now! A potent NLRP3 inhibitor effective against both MCC950-sensitive and -resistant inflammation #chembiol

Structural basis of adenosine 2A receptor-balanced signaling activation relies on allosterically mediated structural dynamics Guo et al. discovered that the activation of adenosine 2A receptor relies on allosterically mediated dynamic loss of structural order in the intracellular half of the transmembrane domain. The findings provide important insights into GPCR activation mechanism.

Online now! Structural basis of adenosine 2A receptor-balanced signaling activation relies on allosterically mediated structural dynamics #chembiol

A covalent inhibitor targeting Cys16 on RhoA in colorectal cancer RhoA is a cancer target in colorectal cancer (CRC) but remains undrugged. Koo et al. identified CL16, which covalently targets the unique Cys16 on RhoA subfamily. CL16 binding effectively inhibits RhoA protein, resulting in promising anticancer and anti-metastatic effects. This study highlights RhoA Cys16 as a targetable hotspot for CRC treatment.

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A base editor facilitates simultaneous purine and pyrimidine substitutions for ex vivo and in vivo mutagenesis screens He et al. developed a base editor, ACGBEmax, by fusing engineered DNA deaminases and glycosylases, enabling simultaneous substitution of A, C, and G bases. ACGBEmax enables in situ generation of diverse variants, supporting efficient mutagenesis screening in cultured cells and mouse liver.

Online now! A base editor facilitates simultaneous purine and pyrimidine substitutions for ex vivo and in vivo mutagenesis screens #chembiol

Pharmacologic interrogation of USP28 cellular function in p53 signaling Bratt, Kilgas et al. describe the SAR-driven design of CAS-010, a selective USP28 probe, alongside a control compound and an inhibitor-resistant mutant. They show that USP28 inhibition mimics p53 pathway loss, reducing p53 transcriptional activity and disrupting 53BP1-USP28 binding, providing mechanistic insight into USP28’s role in p53 signaling.

Online now! Pharmacologic interrogation of USP28 cellular function in p53 signaling #chembiol

BLOC-1 and BORC: Complex regulators of endolysosomal dynamics BLOC-1 and BORC are structurally related complexes that regulate endolysosomal dynamics. De Pace et al. review recent advances in their structure, evolution, and function, highlighting their essential roles in organelle maturation, motility, fusion, tubulation, and biogenesis, and their links to human disease.

Online now! BLOC-1 and BORC: Complex regulators of endolysosomal dynamics #chembiol

An adjuvant database for preclinical evaluation of vaccines and immunotherapeutics http://dlvr.it/TMdVqb

Inhibiting cancer metastasis with water-solubilized membrane receptor CXCR4QTY-Fc as a molecular trap http://dlvr.it/TMdRlQ

Engineering affinity-matured variants of an anti-polysialic acid monoclonal antibody with superior cytotoxicity-mediating potency http://dlvr.it/TMdNRC

A method for the detection and enrichment of endogenous cereblon substrates http://dlvr.it/TMdKHq

Robust antitumor treatment driven by lock-and-key biorecognition of dynamic cyclic diselenide-guided chiral prodrug self-assembly http://dlvr.it/TMcgcg

Targeting the MYC oncogene with a selective bi-steric mTORC1 inhibitor elicits tumor regression in MYC-driven cancers http://dlvr.it/TMcdJZ

RENBP inhibition amplifies metabolic glycan labeling efficiency of antigen-presenting cells in vitro and in vivo http://dlvr.it/TMcZly