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Beyond Kinase Inhibition: From Catalytic Blockade to Control of Protein Fate. 超越激酶抑制：从催化阻断到蛋白质命运的控制。
IF 1.4 4区 化学
Chimia Pub Date : 2026-08-19 DOI: 10.2533/chimia.2026.501
Johan Diepeveen, Zuzanna Kozicka
{"title":"Beyond Kinase Inhibition: From Catalytic Blockade to Control of Protein Fate.","authors":"Johan Diepeveen, Zuzanna Kozicka","doi":"10.2533/chimia.2026.501","DOIUrl":"https://doi.org/10.2533/chimia.2026.501","url":null,"abstract":"<p><p>Kinase inhibitors are a cornerstone of modern drug discovery, with more than 100 approved compounds which have had a transformative impact in precision oncology and inflammatory disease. Their success has rested largely on small-molecule control of catalytic activity through ATP-site engagement; a framework that leaves important biology unaddressed, including non-catalytic kinase functions, resistance driven by active-site mutation, and the limits of selectivity imposed by pocket conservation. Against this backdrop, the observation that kinase inhibitors can reduce target protein abundance has gained new mechanistic depth. Chaperone deprivation, supercharging of native degradation circuits, and context-dependent mutant-selective depletion mark distinct routes through which inhibitor binding can intersect with cellular proteostasis. The kinase inhibitor CR8 extends this logic into chemically encoded degradation: CR8 acts as a molecular glue degrader by creating, within the ligand-bound kinase complex, a composite surface that directly recruits a ubiquitin ligase, resulting in cyclin K degradation. Thalidomide analogues can degrade kinases through scaffolds that do not bind the kinase in isolation: ligase-binding compounds that recruit neosubstrate kinases through recognition of structural surface degrons. Deliberately engineered PROTACs encode ligase-target proximity through heterobifunctional architecture to convert kinase binders into degraders. Beyond degradation, induced-proximity mechanisms - from the clinically established rapamycin to bifunctional molecules that redirect kinase activity or restrict inhibition to tumour cells - show how small molecules can reshape kinase interaction states rather than simply block active sites. Together, these examples define an expanding pharmacological vocabulary for kinase drug discovery: one that asks not only whether a molecule inhibits its target kinase, but how ligand binding rewires protein stability, interactions, localisation, and function.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"80 7-8","pages":"501-508"},"PeriodicalIF":1.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
There's Still Plenty to Do in Photocatalysis. 光催化还有很多工作要做。
IF 1.4 4区 化学
Chimia Pub Date : 2026-08-19 DOI: 10.2533/chimia.2026.458
Julian G West
{"title":"There's Still Plenty to Do in Photocatalysis.","authors":"Julian G West","doi":"10.2533/chimia.2026.458","DOIUrl":"https://doi.org/10.2533/chimia.2026.458","url":null,"abstract":"<p><p>Photocatalysis has undeniable promise for enabling chemical synthesis in a post-fossil resource future; however, this promise has yet to be realized at scale despite over 100 years of interest. Here I propose that this relatively slow progress is rooted in the high chemical complexity of photocatalytic reactions. While the complexity of light absorption and excited state chemistry is a key contributor, our research on Fe/S photocatalysis implicates the efficiency of the many thermal, dark elementary steps being the primary challenge for making a functional reaction. These experiences suggest a paradoxical opportunity in photocatalysis research: one of the richest, most enabling, and most underexplored areas of research is the study of non-photocatalytic steps.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"80 7-8","pages":"458-463"},"PeriodicalIF":1.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Leveraging Radical Ligand Transfer Catalysis for the Construction of Carbon-Heteroatom Bonds. 利用自由基配体转移催化构建碳杂原子键。
IF 1.4 4区 化学
Chimia Pub Date : 2026-08-19 DOI: 10.2533/chimia.2026.444
Dmitry Katayev, Anthony J Fernandes
{"title":"Leveraging Radical Ligand Transfer Catalysis for the Construction of Carbon-Heteroatom Bonds.","authors":"Dmitry Katayev, Anthony J Fernandes","doi":"10.2533/chimia.2026.444","DOIUrl":"https://doi.org/10.2533/chimia.2026.444","url":null,"abstract":"<p><p>Radical ligand transfer (RLT) has emerged as a powerful strategy for the selective construction of carbon-heteroatom bonds through the interception of carbon-centred radicals by redox-active metal complexes. This review highlights recent contributions from our group to RLT-mediated catalysis synergized with electrochemical, photochemical, and mechanochemical activation modes. These RLT-based strategies enabled the development of electrochemical halonitration reactions, photoredox nitrative difunctionalization, and carbochlorination of alkenes, and more recently, mechanochemical nitronitrooxylation, and vicinal dehalogenation reactions. Together, these studies establish RLT as a versatile and sustainable platform for radical-mediated carbon-heteroatom bond formation.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"80 7-8","pages":"444-449"},"PeriodicalIF":1.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Electrochemical Detection Approaches Targeting Single Intact Virions. 针对单个完整病毒粒子的电化学检测方法。
IF 1.4 4区 化学
Chimia Pub Date : 2026-08-19 DOI: 10.2533/chimia.2026.487
Róbert E Gyurcsányi
{"title":"Electrochemical Detection Approaches Targeting Single Intact Virions.","authors":"Róbert E Gyurcsányi","doi":"10.2533/chimia.2026.487","DOIUrl":"https://doi.org/10.2533/chimia.2026.487","url":null,"abstract":"<p><p>Beyond emerging diagnostic applications, intact-virus detection is essential for understanding viral pathogenesis, host-pathogen interactions, and vaccine development. This review highlights in a timeline-based perspective the progress in electrochemical detection of intact virions, focusing on single-virion sensitivity. By directly probing intact viral particles rather than molecular surrogates, nanopore-based resistive-pulse sensing and nano-impact electrochemistry have emerged as versatile virus-counting strategies, enabling selective identification, quantitation, and characterization of morphological and chemical heterogeneity without ensemble averaging. Their potential for calibration-free quantitation, integration with microfluidics, in situ preconcentration, advanced signal processing, and artificial intelligence positions electrochemical platforms as powerful tools for virus analysis.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"80 7-8","pages":"487-493"},"PeriodicalIF":1.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Adventures in Chemical Space: From Targets to Drugs to Design Principles. 化学领域的冒险：从目标到药物再到设计原则。
IF 1.4 4区 化学
Chimia Pub Date : 2026-08-19 DOI: 10.2533/chimia.2026.464
Henrik Möbitz
{"title":"Adventures in Chemical Space: From Targets to Drugs to Design Principles.","authors":"Henrik Möbitz","doi":"10.2533/chimia.2026.464","DOIUrl":"https://doi.org/10.2533/chimia.2026.464","url":null,"abstract":"<p><p>This manuscript traces my journey through computational medicinal chemistry, showing how mechanistic and structural insights and physicochemical reasoning enable the translation of challenging targets into drugs and general design principles. The central theme, conformational analysis, links on-target potency via pre-organization of the bioactive conformation with physics-based physicochemical property prediction. This strategy can unlock dramatic gains in lipophilic efficiency and pharmacokinetic properties through the judicious addition of single atoms. This principle is extended to proteins, particularly kinases, where discrete conformational states can explain binding modes and kinetics. Binding to inactive conformations is linked to slow-on/ slow-off kinetics and can be engineered through ligand design or protein mutations. The manuscript summarizes principles of oral bioavailability in beyond-Rule-of-5 (bRo5) space, highlighting neutral polarity as a key determinant of permeability and exposure. Marketed oral bRo5 drugs and the lead optimization campaigns of first in class representatives converge on a polarity-lipophilicity sweet spot. Finally, nonclassical zwitterions represent a general design strategy to reconcile low lipophilicity with high permeability, supported by strong agreement between computation and experiment.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"80 7-8","pages":"464-472"},"PeriodicalIF":1.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Highly Atroposelective Negishi Coupling Enables the Commercial Manufacturing Process of Divarasib. 高atroopselective根岸偶联使Divarasib的商业化生产过程成为可能。
IF 1.4 4区 化学
Chimia Pub Date : 2026-08-19 DOI: 10.2533/chimia.2026.450
Stephan Bachmann, Raphael Bigler, Danis Kaldre, Dominique Kummli, René Lebl, David Linder, Ugo Orcel, Isabelle Prévot, Jörg Sedelmeier
{"title":"A Highly Atroposelective Negishi Coupling Enables the Commercial Manufacturing Process of Divarasib.","authors":"Stephan Bachmann, Raphael Bigler, Danis Kaldre, Dominique Kummli, René Lebl, David Linder, Ugo Orcel, Isabelle Prévot, Jörg Sedelmeier","doi":"10.2533/chimia.2026.450","DOIUrl":"https://doi.org/10.2533/chimia.2026.450","url":null,"abstract":"<p><p>In this publication, we highlight our development efforts that resulted in the commercial manufacturing route of divarasib (1), a highly potent KRAS G12C inhibitor currently undergoing phase III clinical trials. Most prominently, our process landmarks, the first example of a highly atroposelective Negishi coupling at scale, allowing isolation of the step product (Ra)-4 as a single isomer without chromatography. The implementation of a continuous process for the metalation steps of the atroposelective Negishi coupling allowed for the elimination of the cryogenic reaction conditions from the manufacturing process. Furthermore, we detail improvements for the other chemical steps resulting in an impressive yield increase (factor of 6) and process mass intensity (PMI) reduction (factor of 39) for this sequence.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"80 7-8","pages":"450-457"},"PeriodicalIF":1.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Homogeneous Ruthenium-Catalyzed Carbonyl Groups Selective Hydrogenation Towards F&F Industrial Applications. 均相钌催化羰基选择性加氢在F工业中的应用。
IF 1.4 4区 化学
Chimia Pub Date : 2026-08-19 DOI: 10.2533/chimia.2026.494
Philippe Dupau
{"title":"Homogeneous Ruthenium-Catalyzed Carbonyl Groups Selective Hydrogenation Towards F&amp;F Industrial Applications.","authors":"Philippe Dupau","doi":"10.2533/chimia.2026.494","DOIUrl":"https://doi.org/10.2533/chimia.2026.494","url":null,"abstract":"<p><p>Over the past decades, dsm-firmenich has devoted substantial efforts towards continuous perfumery ingredients and production sustainability improvement through the implementation of green chemistry principles, generally leading to safer, more efficient but also cost-effective industrial chemical processes. Among the numerous examples of innovative homogeneous and heterogeneous catalytic methodologies that have been implemented over the years, we herein provide some insights into more than 20 years of discovery and development in selective carbonyl group hydrogenation reactions for the replacement of waste generating stoichiometric methods, allowing highly efficient access to a large variety of unsaturated alcohols as widespread synthetic intermediates or final ingredients in the Flavor and Fragrance (F&F) industry.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"80 7-8","pages":"494-500"},"PeriodicalIF":1.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Light-Induced Cancer Therapy. 光诱导癌症治疗。
IF 1.4 4区 化学
Chimia Pub Date : 2026-08-19 DOI: 10.2533/chimia.2026.509
Lukas Schneider
{"title":"Light-Induced Cancer Therapy.","authors":"Lukas Schneider","doi":"10.2533/chimia.2026.509","DOIUrl":"https://doi.org/10.2533/chimia.2026.509","url":null,"abstract":"<p><p>Photodynamic therapy (PDT) and photothermal therapy (PTT) are promising light-induced approaches for cancer treatment. This article outlines the historical development of PDT and summarizes the underlying photophysical and photochemical mechanisms responsible for reactive oxygen species (ROS) generation and tumour destruction. Major classes of clinically approved and emerging photosensitizers (PSs) are discussed together with important design criteria and current limitations. In addition, the principles of PTT, including its oxygen-independent mechanism and major classes of photothermal agents (PTAs), are presented. Finally, current challenges and future perspectives regarding selectivity, tissue penetration, biocompatibility, and clinical translation of light-induced therapies are highlighted.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"80 7-8","pages":"509-515"},"PeriodicalIF":1.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unified Gold-Catalyzed Cyclization Approach Towards Isothiazoles from Propargylic Sulfinamides. 统一金催化环化从丙炔亚胺制备异噻唑的方法。
IF 1.4 4区 化学
Chimia Pub Date : 2026-08-19 DOI: 10.2533/chimia.2026.473
Nada Saïdi, Thomas Simonet, Daniel P Kloer, Mark Montgomery, Myriem El Qacemi
{"title":"Unified Gold-Catalyzed Cyclization Approach Towards Isothiazoles from Propargylic Sulfinamides.","authors":"Nada Saïdi, Thomas Simonet, Daniel P Kloer, Mark Montgomery, Myriem El Qacemi","doi":"10.2533/chimia.2026.473","DOIUrl":"https://doi.org/10.2533/chimia.2026.473","url":null,"abstract":"<p><p>Isothiazoles are valuable heterocycles in agrochemical and pharmaceutical research, yet they remain synthetically less accessible than their isoxazole counterparts. We report here a gold-catalyzed cyclization of propargylic N-tert-butanesulfinamides that provides direct and efficient access to isothiazoles under mild conditions. The transformation proceeds through an unusual cascade: cationic gold activation of the alkyne triggers a 5-endo-dig ring closure with sulfur as the nucleophile followed by irreversible loss of the tert-butyl group and dehydrative aromatization. The substrate scope encompasses a range of alkyl and aryl substituents, affording isothiazoles in yields of up to 79%. Reaction monitoring and isolation of key intermediates establish that the cyclic sulfinamide is a direct precursor to the aromatic product and that protic solvents, particularly acetic acid, facilitate the cascade of events, dramatically reducing reaction times. A complementary base-catalyzed pathway from CF3-substituted substrates selectively delivers cyclic sulfoximines, demonstrating that both heterocyclic classes are accessible from a common precursor by simply switching the activation mode. These results originate from a serendipitous observation made during insecticide research at Syngenta and have broader implications for the design of sulfur-containing heterocyclic scaffolds.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"80 7-8","pages":"473-478"},"PeriodicalIF":1.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Editorial. 社论。
IF 1.4 4区 化学
Chimia Pub Date : 2026-08-19 DOI: 10.2533/chimia.2026.441
Christian G Bochet
{"title":"Editorial.","authors":"Christian G Bochet","doi":"10.2533/chimia.2026.441","DOIUrl":"https://doi.org/10.2533/chimia.2026.441","url":null,"abstract":"","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"80 7-8","pages":"441"},"PeriodicalIF":1.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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