RSC medicinal chemistry最新文献

{"title":"In vitro and in vivo ADME of heterobifunctional degraders: a tailored approach to optimize DMPK properties of PROTACs©†","authors":"Christine Katharina Maurer, Zhizhou Fang, Christina Schindler, Gianna Pohl, Fouzia Machrouhi-Porcher, Marc Lecomte, Carl Petersson and Heide Marika Duevel","doi":"10.1039/D4MD00854E","DOIUrl":"10.1039/D4MD00854E","url":null,"abstract":"<p >Proteolysis-targeting chimeras (PROTACs©) have recently emerged as a promising new drug modality. Residing beyond the rule-of-five space, they pose challenges in terms of physicochemical properties. With this study, we contribute to enhancing the understanding of their early ADME characterization. For permeability assessment, transwell assays such as Caco-2 remain challenging. Although the addition of serum may reduce unspecific binding and improve recovery, the assay was not found predictive for absorption. As a surrogate, we propose to focus optimization on molecular descriptors and support a preferred space for oral PROTACs© with ≤3 H-bond donors (HBDs), molecular weight (MW) ≤950 Da and number of rotatable bonds ≤12. We have developed a predictive score serving as initial guidance for design and prioritization according to this property space. In addition, the reduction of exposed polar surface area, <em>e.g.</em> through shielding of HBDs, is a powerful approach to optimize permeability. Using standard small molecule-based methods for <em>in vitro</em>–<em>in vivo</em> extrapolation (IVIVE) of intrinsic clearance (CL<small>_int</small>) with experimentally determined hepatocyte CL<small>_int</small> and fraction unbound in plasma, and predicted fraction unbound in the incubation (<em>f</em><small>_u,inc</small>), a systematic under-prediction from mouse hepatocytes was observed for PROTACs©. In line with our observation that the Kilford equation was not suitable for PROTAC© <em>f</em><small>_u,inc</small> prediction, this bias could be overcome by using experimentally determined <em>f</em><small>_u,inc</small>. Taken together, this study suggests a tailored <em>in vitro</em> DMPK discovery assay cascade and frontloading <em>in vivo</em> studies. It also underlines the need for inclusion of surrogate permeability descriptors and experimentally determined values for IVIVE of CL<small>_int</small>.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 4","pages":" 1746-1757"},"PeriodicalIF":4.1,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxazole and isoxazole-containing pharmaceuticals: targets, pharmacological activities, and their SAR studies.","authors":"Shanshan Li, Yiou Mei, Luchen Jiang, Xueyan Yang, Wei Zeng, Yunfei Du","doi":"10.1039/d4md00777h","DOIUrl":"10.1039/d4md00777h","url":null,"abstract":"<p><p>Oxazole, a five-membered aromatic heterocycle featuring a nitrogen and an oxygen atom separated by a carbon atom, and its isomer isoxazole, with directly attached oxygen and nitrogen atoms, have been pivotal in medicinal chemistry. Over the past few decades, the U.S. Food and Drug Administration (FDA) has approved more than 20 drugs containing these nuclei for various clinical conditions, including Tafamidis and Oxaprozin. Due to their unique physicochemical properties, these drugs often exhibit superior pharmacokinetic profiles and pharmacological effects compared to those with similar heterocycles. This review provides a comprehensive overview of all FDA-approved drugs containing oxazole and isoxazole nuclei, focusing on their pharmacological activities and structure-activity relationships.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards more efficient synthetic immunomodulators: biological characterization and mechanism of action of monosaccharide-derived TLR4 agonists.","authors":"Ana Rita Franco, Zaineh Aladailleh, Alessio Romerio, Alice Italia, Federico Lami, Mohammed Monsoor Shaik, Natalia Skupinska, Valentina Artusa, Grisha Pirianov, Francesco Peri","doi":"10.1039/d4md00950a","DOIUrl":"10.1039/d4md00950a","url":null,"abstract":"<p><p>Toll-like receptors (TLRs), including TLR4, play a crucial role in innate immunity activation, and small molecular TLR4 activators (agonists) are in the preclinical and clinical phases of development as vaccine adjuvants or tumor immunotherapeutics. Recently, we generated novel glucosamine-derived compounds, FP molecules, that are active as TLR4 agonists. Despite their chemical structure differing from LPS, some of these compounds, including compound FP18, mimicked the biological activity of LPS and its capacity to activate TLR4 and its downstream pathways. In contrast to FP18, compound FP20 showed immunostimulant activity that was only partially due to TLR4 agonism. This activity was mainly associated with NLRP3 inflammasome activation. We generated a panel of glycosylated FP20 derivatives (glyco-FP20) bearing different monosaccharides linked to C6 of the glucosamine. The biological activity of glyco-FP20 was related to TLR4 activation, as assessed from preliminary experiments in HEK-Blue cells. We presented a comprehensive study of the mechanism of action of glyco-FP20 derivatives and their effect on TLR4 signalling, leading to macrophage M1 polarisation and pyroptosis in THP-1 derived macrophages. Results revealed that, similarly to LPS and differently from FP20, glyco-FP20 derivatives were potent TLR4 agonists inducing TLR4/MyD88 signalling pathways that led to M1 macrophage polarisation, associated with NF-kB activation/translocation and release of a number of proinflammatory mediators in THP-1-derived macrophages. In particular, compound FP20 Rha activated TLR4/TRIF signalling, associated with phosphorylation of STAT1/IRF3, leading to the production of IFN-β in THP-1-derived macrophages. Furthermore, using a specific GSD inhibitor (U73), we demonstrated the ability of FP20 and glyco-FP20 to induce GSD-dependent pyroptosis, which was associated with IL-1β/IL-18 and LDH release in THP-1-derived macrophages. These results show that the optimization of FP20 glycosylation can increase the biological potency of the parent molecule and can be used in preclinical development as vaccine adjuvants or macrophage-based cancer immunotherapy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel potent and selective dual acetylcholinesterase inhibitors: <i>N</i>-substituted theobromine and theophylline derivatives.","authors":"Brunella Biscussi, Eduardo J Cueto-Díaz, Concepción Pérez, María Isabel Rodríguez-Franco, Ana Paula Murray","doi":"10.1039/d5md00031a","DOIUrl":"https://doi.org/10.1039/d5md00031a","url":null,"abstract":"<p><p>Methylxanthines and their derivatives are of great interest due to their diverse biological activities. In this work, a new series of twenty-eight semisynthetic theobromine and theophylline derived compounds were designed and synthesized by applying a simple and efficient strategy. First, the corresponding methylxanthine was reacted with a dibromoalkane (<i>n</i> = 3, 5-8) and subsequently, the brominated intermediate was reacted with an amine, including pyrrolidine, piperidine, diethylamine, methylpiperazine, 1-(2-aminoethyl)pyrrolidine, 1-(2-aminoethyl)piperidine, 2-(1-methylpyrrolidin-2-yl)ethanamine, 1-benzylpiperidin-4-amine, 1-benzylpiperidin-4-yl-methanamine, and 2-(1-benzylpiperidin-4-yl)ethan-1-amine. The two synthetic steps were carried out in very short times using a microwave reactor. The biological activity of the new compounds was evaluated on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases (MAO-A, MAO-B) and beta-secretase (BACE-1). The majority of the new derivatives showed potent and selective <i>in vitro</i> AChE inhibition. Compounds 21, 28 and 30 exhibited the strongest effect on both electric eel and human AChE enzyme, with IC₅₀ values on the low nanomolar scale. The kinetic study of compound 28 in <i>h</i>AChE displayed a mixed inhibition mechanism, suggesting a simultaneous interaction with both the CAS and PAS of the enzyme. This experimental binding mode is consistent with the results of docking and molecular dynamics modelling studies, where it was observed that the piperidinium fragment of 16, 21, 28 and 32 was located at the CAS, whereas the xanthine fragment of each inhibitor interacted with Trp286 in the PAS. These results indicate that these novel xanthine analogues act as selective and potent AChE inhibitors that could also prevent the precipitation of the aberrant Aβ peptide. These properties, in conjunction with their <i>in silico</i> good pharmacokinetic profiles, make these molecules promising lead compounds for the development of new effective drugs against several forms of dementia.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of isoquinoline-tethered quinazoline derivatives with enhanced HER2 inhibition over EGFR.","authors":"Jung Wuk Lee, Chang Gyun Im, Ji Min Lee, Minsang Cho, Mingi Kim, Kiho Lee, Hien Thi Thu Nguyen, Jiwon Seo, Ji Hae Seo, Kyung Hoon Min","doi":"10.1039/d5md00025d","DOIUrl":"10.1039/d5md00025d","url":null,"abstract":"<p><p>Human epidermal growth factor receptor 2 (HER2) is a critical therapeutic target for HER2-positive or HER2-dependent cancers. While several HER2 kinase inhibitors have been identified, achieving high selectivity for HER2 over EGFR remains a significant challenge. In this study, we aimed to develop HER2-selective inhibitors with enhanced cellular activity. To improve the limited cellular activity of derivatives with a quinoline moiety against HER2, we synthesized a novel series of derivatives by bioisosteric replacement. These derivatives demonstrated significantly improved selectivity for HER2 over EGFR, with a 7- to 12-fold enhancement compared to lapatinib in kinase assays. Furthermore, they exhibited enhanced cellular activity, leading to improved anti-proliferative effects against HER2-dependent SKBR3 cells. Notably, the representative compound 14f demonstrated more potent inhibition of HER2 phosphorylation at the cellular level compared to lapatinib. Additionally, compound 14f exhibited high HER2 selectivity, significantly inhibited colony formation in SKBR3 cells, and displayed good metabolic stability. These findings suggest the potential of these compounds as novel therapeutic candidates for HER2-positive cancers.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11886616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Donepezil-based rational design of <i>N</i>-substituted quinazolinthioacetamide candidates as potential acetylcholine esterase inhibitors for the treatment of Alzheimer's disease: <i>in vitro</i> and <i>in vivo</i> studies.","authors":"Ahmed A Al-Karmalawy, Ahmed F Mohamed, Heba Nasr Shalaby, Ayman Abo Elmaaty, Riham A El-Shiekh, Mohamed A Zeidan, Radwan Alnajjar, Abdullah Yahya Abdullah Alzahrani, Mohammed H Al Mughram, Moataz A Shaldam, Haytham O Tawfik","doi":"10.1039/d4md00778f","DOIUrl":"https://doi.org/10.1039/d4md00778f","url":null,"abstract":"<p><p>Alzheimer's disease (AD) stands as one of the most outstanding progressive neurodegenerative disorders. Obviously, acetylcholine esterase (AChE) is the primary enzyme responsible for breaking down acetylcholine (ACh) with a much more prominent effect than butyrylcholine esterase (BuChE). Hence, novel quinazoline derivatives (3a-p) were designed and synthesized as AChE inhibitors for AD treatment. The newly synthesized quinazoline derivatives (3a-p) were pursued for their inhibitory potential towards both AChE and BuChE. Notably, compound 3e displayed the highest inhibitory potential towards AChE (IC₅₀ = 9.26 nM) surpassing donepezil (IC₅₀ = 16.43 nM). On the other side, compound 3e effectively negated the decline in memory acquisition and retention instigated by ICV administration of streptozotocin (STZ) in mice, an effect that was comparable to that produced by donepezil. Moreover, compound 3e, reduced BACE1 by 51.08% (<i>p</i> < 0.0001), Aβ42 by 52.47% (<i>p</i> < 0.0001), and p(Ser199)-tau by 69.16% (<i>p</i> < 0.0001) compared to STZ mice. Such effects were similar to those of donepezil which reduced all 3 parameters by 57.53%, 58.5%, and 66.78%, respectively, compared to STZ mice. Furthermore, molecular docking studies showed that the superimposition view clarified the similar binding mode of both 3e and the co-crystallized donepezil at the AChE binding pocket. Moreover, the docked complexes (3e-AChE and 3e-BuChE) were further subject to molecular dynamics simulations for 100 ns. In addition, eligible pharmacokinetic profiles as well as feasible BBB penetration were anticipated for compound 3e using ADME and BBB permeation prediction studies. Accordingly, the synthesized compounds, in particular compound 3e, can be treated as promising lead compounds for AD treatment with future further optimization.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and <i>in vitro</i> evaluations of new cyclotriphosphazenes as safe drug candidates.","authors":"Elif Yıldız Gül, Büşra Tiryaki, Buse Köse, Nuri Öztürk, Elif Okutan, Burcu Dedeoğlu, Esra Tanrıverdi Eçik","doi":"10.1039/d4md00885e","DOIUrl":"https://doi.org/10.1039/d4md00885e","url":null,"abstract":"<p><p>Although it is possible to discover new drug candidate molecules using <i>in silico</i> approaches, chemical synthesis followed by screening of their functions is still at the center of bioactive molecule discovery. While determining the potential effects of compounds on target signaling molecules or pathways, assessing their effects on the circadian rhythm is also very important for determining the efficacy of drug candidates because they control most of the signaling pathways. Herein, new members of the biocompatible cyclotriphosphazene family were prepared, and their <i>in vitro</i> biological activities and effects on circadian rhythm were evaluated for the first time. In particular, new cyclotriphosphazene derivatives carrying morpholine, thiomorpholine and triazole groups were designed and synthesized, and their chemical structures were characterized using appropriate spectroscopic methods. Cellular toxicity analyses of the compounds were performed using different biological methods, such as determination of IC₅₀ values, calculation of population doubling times, and colony formation patterns. Subsequently, the effects of the compounds on the cell cycle were analyzed using the flow cytometry technique. Finally, the effects of the synthesized compounds on circadian rhythm were determined using a real-time bioluminescence approach. Based on these studies, it was determined that some compounds demonstrated varying degrees of antiproliferative activity, with the most potent compounds causing G₂/M phase arrest. Additionally, most derivatives had no adverse effects on the circadian rhythm, indicating their potential for safe therapeutic application in targeting cell proliferation. Furthermore, an important pharmacological characteristic of the drug candidate molecules, namely, membrane permeability in terms of log <i>P</i> values, was assessed. In conclusion, these novel cyclotriphosphazene-based compounds are a class of circadian rhythm-safe drug candidate compounds.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small molecule targeted protein degradation <i>via</i> the UPS: venturing beyond E3 substrate receptors.","authors":"Renyu Guo, Fukang Yang, Emily C Cherney","doi":"10.1039/d4md00718b","DOIUrl":"10.1039/d4md00718b","url":null,"abstract":"<p><p>The ubiquitin proteasome system (UPS) has been successfully hi-jacked by both bifunctional and monovalent small molecules to affect the degradation of proteins that were once considered undruggable. This field has primarily focused on the targeted recruitment of proteins to substrate receptors on E3 ubiquitin ligases, which are only one part of the UPS. More recently, the field has begun to explore recruitment to other types of UPS proteins including E2 ubiquitin-conjugating enzymes, substrate adaptor proteins within the E3 complex, chaperone proteins that associate with E3s, proteasomal subunits, and proteasome-associated proteins. While these approaches are relatively nascent compared to more traditional E3 substrate receptor-based degradation, these approaches are starting to show promise and could offer unique advantages. This review will cover key findings in small molecule UPS-mediated targeted protein degradation (TPD) affected by co-opting proteins beyond traditional E3 substrate receptors.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pan-cancer analysis of LRG1 and its potential role in kidney renal clear cell carcinoma†","authors":"Ziwen Lei, Shiyu Song, Yizhuo Geng, Bian Liu, Yongzheng Li, Huan Min, Saiyang Zhang and Yingqiu Qi","doi":"10.1039/D4MD00940A","DOIUrl":"10.1039/D4MD00940A","url":null,"abstract":"<p >Leucine-rich α-2 glycoprotein 1 (LRG1) is a secreted glycoprotein implicated in various diseases, yet its role across multiple cancers remains insufficiently explored. Consequently, we conducted a comprehensive bioinformatics analysis, exploring LRG1 expression patterns, prognostic implications, and potential therapeutic associations in a pan-cancer context. Additionally, we collected gene expression and clinical data from patients with kidney renal clear cell carcinoma (KIRC) from TCGA, conducting gene set enrichment analysis (GSEA) and Cox proportional hazards regression analysis to explore the potential regulatory role of LRG1 in KIRC. Our study revealed that LRG1 expression is upregulated in 18 cancer types, with elevated levels correlating with poor prognostic outcomes in several cancers, notably KIRC. Epigenetic analysis showed hypomethylation in the LRG1 promoter region, potentially contributing to the overexpression of LRG1. Moreover, LRG1 expression was linked to immunotherapeutic responses and altered drug sensitivities, particularly influencing the efficacy of tyrosine kinase inhibitors. In KIRC, high LRG1 expression was associated with the activation of key pathways, including angiogenesis, epithelial–mesenchymal transition (EMT), and hypoxia signalling. We identified key gene pairs interacting with LRG1 in KIRC, including CARD14 and CYP8B1, with CARD14 overexpression correlating with poorer clinical outcomes and CYP8B1 indicating a favourable prognosis. In conclusion, LRG1 emerges as a potential biomarker for prognosis and immunotherapy responsiveness in both pan-cancer and KIRC contexts. This study provides a theoretical foundation for further research on the therapeutic potential of target regulating LRG1 in cancer treatment.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 4","pages":" 1781-1796"},"PeriodicalIF":4.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of new imidazole[1,2-<i>a</i>] pyridine derivatives as CDK9 inhibitors: design, synthesis and biological evaluation.","authors":"Zihan Sun, Shijun Sun, Xiayu Li, Xiang Li, Chuang Li, Li Tang, Maosheng Cheng, Yang Liu","doi":"10.1039/d5md00016e","DOIUrl":"10.1039/d5md00016e","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a highly aggressive and extensive malignancy. Presently, targeting the transcriptional regulation of cyclin-dependent kinase 9 (CDK9) is a promising therapeutic approach. Herein, twenty-five compounds (LA-1-LA-13 and LB-1-LB-12) were designed and synthesized with <b>AZD5438</b> as the lead compound using an imidazole[1,2-<i>a</i>] pyridine skeleton. Compound LB-1 exhibited potent CDK9 inhibition and induced apoptosis in the HCT116 cell line. Moreover, compared with <b>AZD5438</b>, LB-1 demonstrated highly selective CDK9 inhibitory activity, with an IC₅₀ value of 9.22 nM. Accordingly, compound LB-1 could be further developed as a selective, target-oriented CDK9 inhibitor for colorectal cancer.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}