European Journal of Medicinal Chemistry最新文献

{"title":"Discovery of KRAS-G12D degraders via exploration of various E3 ligases","authors":"Hyerin Yim ,&nbsp;Xiangyang Song ,&nbsp;Yue Zhong,&nbsp;Jacqueline Hu,&nbsp;Yan Xiong,&nbsp;Jian Jin","doi":"10.1016/j.ejmech.2026.118635","DOIUrl":"10.1016/j.ejmech.2026.118635","url":null,"abstract":"<div><div>PROteolysis TArgeting Chimera (PROTAC) is a promising modality for targeted protein degradation. Although 600+ E3 ligases exist in the human genome, most PROTACs exploit a very limited set of E3 ligases, primarily CRBN and VHL. In this study, we designed, synthesized and evaluated a series of KRAS-G12D degraders that recruit one of four E3 ligases (CRBN, VHL, DCAF1, or KLHDC2) using a common KRAS-G12D binder derived from the KRAS-G12D inhibitor MRTX1133. Through this structure–activity relationship (SAR) study, we discovered two potent degraders: <strong>30</strong> (CRBN-based) and <strong>41</strong> (VHL-based), both of which effectively degraded KRAS-G12D and suppressed downstream signaling. By introducing a triazole-based VHL ligand, we subsequently discovered <strong>43</strong>, which showed improved degradation and antiproliferative activity comparable to a previously reported KRAS-G12D degrader. In contrast, KLHDC2- and DCAF1-based degraders failed to induce KRAS-G12D degradation, potentially due to suboptimal ternary complex formation or insufficient E3 ligase compatibility. These findings highlight the importance of E3 ligase selection in the development of effective KRAS-G12D degraders.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118635"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a new protein-RNA interaction inhibitor targeting the KH34 region of the insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2/IMP2)","authors":"Aylin Berwanger ,&nbsp;Konrad Wagner ,&nbsp;Simon Both ,&nbsp;Andreas M. Kany ,&nbsp;Kyana Mazlom ,&nbsp;Anna K.H. Hirsch ,&nbsp;Alexandra K. Kiemer ,&nbsp;Martin Empting","doi":"10.1016/j.ejmech.2026.118624","DOIUrl":"10.1016/j.ejmech.2026.118624","url":null,"abstract":"<div><div>Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2/IMP2) plays a crucial role in the posttranscriptional regulation of gene expression and influences various cellular processes including cell growth, differentiation, and metabolism. Dysregulation of IMP2 has been associated with several diseases, including cancer and metabolic disorders. Targeting IMP2 with small molecules is a promising therapeutic strategy. However, the structural diversity of IMP2-targeting compounds remains limited. In this study, we present a comprehensive screening approach with the aim of identifying new structural classes of compounds that can inhibit IMP2 activity, particularly its binding to the KH34 domain. Screening of a chemically diverse library comprising 10,240 compounds using fluorescence polarization–based assays led to the identification of ten primary actives belonging to five distinct structural classes. After rigorous resynthesis and hit validation, only one compound comprising a sulfonamide scaffold reproducibly inhibited the KH34–RNA interaction <em>in vitro</em>. This hit was further characterized by STD-NMR and <em>in vitro</em> ADME profiling, including solubility, lipophilicity, metabolic stability, plasma protein binding, and cellular permeability. While this sulfonamide-based inhibitor exhibits clear biochemical activity and a defined binding mode at the KH34 RNA-binding interface, its limited cellular permeability and high plasma protein binding currently preclude cellular efficacy. This work identifies a new structural class of IMP2 KH34 inhibitors serving as a starting point for an ongoing hit-to-lead optimization campaign towards next-generation anti-cancer drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118624"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-activity relationship of steroidal-nitroxide hybrids: Dual-modulators of glucocorticoid receptor signalling and cellular redox state","authors":"Carl P. Soltau ,&nbsp;Ban Qi Tay ,&nbsp;Alexander P. Martyn ,&nbsp;Derek J. Richard ,&nbsp;Mark N. Adams ,&nbsp;Steven E. Bottle","doi":"10.1016/j.ejmech.2026.118655","DOIUrl":"10.1016/j.ejmech.2026.118655","url":null,"abstract":"<div><div>Inflammation and redox imbalance are hallmarks of many diseases. Here, we report the synthesis and systematic evaluation of steroid-nitroxide hybrid compounds as dual-acting anti-inflammatory and redox-modulating agents. Hybrids were generated <em>via</em> ester (<strong>1a-c</strong>, <strong>2a-b</strong>), amide (<strong>1d-h</strong>), and ether (<strong>3a-c</strong>) linkages at the C21 position of corticosteroids prednisolone, cortisol, and dexamethasone. The hybrids exhibit glucocorticoid receptor (GR) activity and suppress IL-6 secretion <em>in vitro</em> at variable potencies, some comparable to commercial corticosteroids. Cellular metabolic evaluation demonstrates various rates of intracellular cleavage for ester- and amide-linked hybrids, while ether-linked hybrids remain intact. Assessment of general reactive oxygen species (ROS) levels <em>via</em> the fluorogenic probe 2′,7′-dichlorofluorescein diacetate (DCFDA) demonstrated linker-dependent pro-oxidative effects, with poorly labile and non-cleavable compounds (<strong>1a</strong>, <strong>3a-c</strong>) causing sustained ROS elevation, while cleavable hybrids produced only transient, recoverable increases. Notably, one hybrid (<strong>1a</strong>) demonstrated higher ROS elevation in A549 cells over normal human fibroblasts (i.e. NFF cells) suggesting certain structural features of this hybrid induce specificity. Live-cell imaging using fluorescent analogues supports the mechanism of intracellular cleavage and efflux for cleavable hybrids, while non-cleavable hybrids remain within the cell. These findings demonstrate that steroidal-nitroxide hybrids harness both anti-inflammatory and redox modulation pathways, positioning them as a novel treatment strategy where dual anti-inflammatory and pro-oxidant strategies are advantageous.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118655"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semi-rigid linkers improve the pharmacokinetic properties and therapeutic efficacy of BET PROTACs for cancer therapy","authors":"Su Yu ,&nbsp;Shichuan Hu ,&nbsp;Weilin Wang ,&nbsp;Chuntao Pan ,&nbsp;Hongjia Zhang ,&nbsp;Cong Zhou ,&nbsp;Yang Liu ,&nbsp;Rui Li","doi":"10.1016/j.ejmech.2026.118644","DOIUrl":"10.1016/j.ejmech.2026.118644","url":null,"abstract":"<div><div>PROTACs offer a novel therapeutic strategy for addressing diseases driven by aberrant expression of pathogenic proteins. In this study, we identified a series of PROTAC molecules capable of degrading BRD2, BRD3, and BRD4. Structure–activity relationship analysis led to the discovery of <strong>CR10</strong>, a highly potent degrader that exhibited remarkable activity in MV4-11 cells. Mechanistic studies demonstrated that <strong>CR10</strong> induced sustained degradation of target proteins <em>via</em> the ubiquitin–proteasome system. In mice models, intraperitoneal administration at 20 mg/kg achieved an exceptional bioavailability of 108.27%. Furthermore, <strong>CR10</strong> significantly inhibited the growth of MV4-11 and A549 xenograft tumors at a dose as low as 2 mg/kg, without apparent toxicity. This semi-rigid linker–containing degrader represented a promising new mechanism-based candidate for the treatment of hematologic malignancies and lung cancer, warranting further investigation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118644"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological evaluation of novel pyrrolo[1,2-b]pyridazin-2(1H)-ones as selective PARP1 inhibitors for cancer therapy","authors":"Qiaolin He ,&nbsp;Jing He ,&nbsp;Xiajuan Huan ,&nbsp;Shanshan Song ,&nbsp;Xiaofei Zhang ,&nbsp;Qian He ,&nbsp;Zehong Miao ,&nbsp;Jinxue He ,&nbsp;Chunhao Yang","doi":"10.1016/j.ejmech.2026.118650","DOIUrl":"10.1016/j.ejmech.2026.118650","url":null,"abstract":"<div><div>Poly-ADP-ribose-polymerase inhibitors (PARPi) hold significant clinical value in the treatment of BRCA-deficient tumors, but their substantial hematological toxicity limits a broader scope of clinical applications. Studies suggest that the toxicity may be associated with selective deficiency between PARP1 and PARP2. In this study, we designed and synthesized a series of inhibitors containing novel pyrrolo[1,2-<em>b</em>]pyridazin-2(1<em>H</em>)-one scaffold selectively targeting PARP1. Among these compounds, <strong>YCH3971</strong> exhibited potent inhibiting activity against PARP1 with an IC₅₀ of 7.52 nM, showing a remarkable subtype selectivity compared with PARP2 (&gt;1000-fold). Also, <strong>YCH3971</strong> possessed a strong antiproliferative activity on BRCA mutant MDA-MB-436 cells with an IC₅₀ of 2.10 nM. However, since the oral bioavailability of <strong>YCH3971</strong> in rats is only 1.2%, we have not yet initiated in vivo efficacy studies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118650"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and optimization of Menin-MLL inhibitors targeting acute myeloid leukemia","authors":"Qitao Xiao ,&nbsp;Yuxian Wang ,&nbsp;Zheyuan Shen ,&nbsp;Jun Mo ,&nbsp;Cong Li ,&nbsp;Rongkuan Jiang ,&nbsp;Jingyu Zhang ,&nbsp;Yubo Zhou ,&nbsp;Xiaowu Dong ,&nbsp;Hanlin Wang ,&nbsp;Tao Liu","doi":"10.1016/j.ejmech.2026.118641","DOIUrl":"10.1016/j.ejmech.2026.118641","url":null,"abstract":"<div><div>A machine learning-guided strategy, which integrated unsupervised structural clustering to identify diverse scaffolds for molecular hybridization followed by synergistic QSAR and molecular docking screening, identified lead compound 7. Guided by this lead, a series of thieno[2,3-<em>d</em>]pyrimidine derivatives were developed as menin inhibitors through several rounds of rational structural optimization. Among them, compound <strong>A13</strong> exhibited potent anti-proliferative activity against MV4-11 cells (0.379 ± 0.182 μM). Besides, mechanistic studies confirmed <strong>A13</strong> disrupts menin-MLL interactions, induces cell differentiation, and selectively inhibits MLL-rearranged (MV4-11, MOLM-13) and DNMT3A/NPM1-mutated (OCI-AML3) leukemia cells. The stable binding mode of A13 with menin was further elucidated by molecular dynamics simulations. Moreover, <strong>A13</strong> exhibited favorable oral pharmacokinetic properties, characterized by rapid absorption (T_max = 1.67 h) and high plasma exposure (AUC_0–t = 2241 ng h/mL), demonstrating its potential as a promising candidate for further preclinical development against MLL-rearranged AML.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118641"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and biological evaluation of Retro-2-based PROTACs reveal PEG-linker length and warhead impact on GSPT1 degradation","authors":"Marine Michon ,&nbsp;Sebastien Curpanen ,&nbsp;Ombeline Pessey ,&nbsp;Robert Thai ,&nbsp;Jean-Charles Gaillard ,&nbsp;Gaëtan Herbette ,&nbsp;Karen Hinsinger ,&nbsp;Daniel Gillet ,&nbsp;Jean Armengaud ,&nbsp;Jean-Christophe Cintrat ,&nbsp;Julien Barbier","doi":"10.1016/j.ejmech.2026.118645","DOIUrl":"10.1016/j.ejmech.2026.118645","url":null,"abstract":"<div><div>PROteolysis TArgeting Chimeras are attracting growing interest in pharmaceutical research thanks to their catalytic and irreversible mechanism, which is capable of targeting proteins previously considered \"undruggable\". These bifunctional molecules hijack the cellular ubiquitin-proteasome system by recruiting E3 ligases (such as CRBN or VHL) to induce the selective degradation of a target protein. Their efficacy has been demonstrated against various disorders and several compounds have reached phase I-III clinical trials, reinforcing their appeal. In the fight against toxins, derivatives of the Retro-2 molecule (active against Shigatoxins, ricin, and various pathogens) have been developed. These molecules act on host cells by disrupting the intracellular trafficking of pathogens, targeting in particular the Sec16A and/or ASNA1 proteins. Our study presents the synthesis and characterization of new chemical probes based on PROTAC technology, combining a CRBN ligand derived from thalidomide, a Retro-2 derivative, and variable-length PEG chain linkers to better understand the mechanism of action of Retro-2-derived molecules. Contrary to initial assumptions, our results do not show proteasome-dependent degradation of the protein targets, but demonstrate that PEG-2 molecules can degrade the translation termination factor GSPT1 despite the normally propitious anchoring of the PEG linker at position 4 of the phthalimide ring. Furthermore, this study shows for the first time that GSPT1 degradation depends on the length of the flexible PEG chain linker.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118645"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of potent human DHRS11 inhibitors and their efficacy against androgen-dependent proliferation and sensitivity to AKT inhibitor Capivasertib of triple-negative breast cancer cells","authors":"Yuri Miyamoto ,&nbsp;Wakana Hirai ,&nbsp;Tomofumi Saka ,&nbsp;Masatoshi Tanio ,&nbsp;Yudai Kudo ,&nbsp;Yuta Yoshino ,&nbsp;Yusuke Nakagawa ,&nbsp;Nao Kobayashi ,&nbsp;Sana Takada ,&nbsp;Takuya Okada ,&nbsp;Naoki Toyooka ,&nbsp;Mahmoud Kandeel ,&nbsp;Nobutada Tanaka ,&nbsp;Akira Ikari ,&nbsp;Satoshi Endo","doi":"10.1016/j.ejmech.2026.118649","DOIUrl":"10.1016/j.ejmech.2026.118649","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer lacking estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Among its heterogeneous subtypes, luminal androgen receptor-positive (LAR) TNBC is driven by androgen signaling and presents limited treatment options. We previously identified dehydrogenase/reductase SDR family member 11 (DHRS11) as a novel enzyme involved in androgen biosynthesis, and demonstrated that Kobochromone A (<strong>KC-A</strong>), a polyphenol isolated from <em>Carex kobomugi</em>, inhibited androgen-driven proliferation in LAR TNBC cells via DHRS11 inhibition and AR downregulation.</div><div>In this study, we synthesized 23 structural derivatives of <strong>KC-A</strong> and identified <strong>WH23</strong> as the most potent DHRS11 inhibitor (IC₅₀ = 37 nM). Molecular docking and MM-PBSA analysis revealed that the 2′-hydroxy group of <strong>WH23</strong> forms a hydrogen bond with His210 of DHRS11, which was validated by site-directed mutagenesis. <strong>WH23</strong> suppressed AR mRNA and protein expression, reduced 11-ketodihydrotestosterone (11KDHT)-induced c-Myc expression, and inhibited proliferation of MDA-MB-453 cells. Additionally, <strong>WH23</strong> inhibited PI3K/AKT signaling, reducing phosphorylation of PDK1, AKT, mTOR, and ERK. Capivasertib (<strong>Cap</strong>), a clinically approved pan-AKT inhibitor, induced DHRS11 expression in MDA-MB-453 cells. Although <strong>Cap</strong> and <strong>WH23</strong> did not show synergistic cytotoxicity in parental cells, <strong>Cap</strong>-resistant (Cap-R) cells, which exhibited elevated DHRS11 and c-Myc expression, showed significant sensitivity to the combination. In Cap-R cells, the combination of <strong>Cap</strong> and <strong>WH23</strong> significantly induced apoptosis, demonstrating a synergistic anticancer effect.</div><div>These findings establish WH23 as a dual-acting compound targeting both androgen biosynthesis and AR signaling, with potential to overcome AKT inhibitor resistance in LAR TNBC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118649"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Marine natural product-inspired 2-(3,4,5-trimethoxybenzoyl)quinazolin-4(3H)-one derivative CHNQD-01522: A novel anti-hepatocellular carcinoma agent targeting colchicine binding site of microtubule","authors":"Peng-Jie Li ,&nbsp;Chao-Jie Wang ,&nbsp;Rui-Qin Zhai ,&nbsp;Ji-Xiu Gao ,&nbsp;Hao-Ran Li ,&nbsp;Jian-Yu Liu ,&nbsp;Mei-Yan Wei ,&nbsp;Yu-Cheng Gu ,&nbsp;Chang-Lun Shao","doi":"10.1016/j.ejmech.2026.118658","DOIUrl":"10.1016/j.ejmech.2026.118658","url":null,"abstract":"<div><div>Microtubule targeting agents are effective in cancer therapy, but current inhibitors face challenges including systemic toxicity and P-glycoprotein (P-gp) mediated drug resistance, underscoring the need for novel microtubule inhibitors. Quinazolin-4(3<em>H</em>)-one alkaloids, with diverse targets, exhibit significant potential for developing novel anti-cancer agents. Herein, inspired by marine quinazolin-4(3<em>H</em>)-one alkaloid penipanoid C, compounds <strong>1‒55</strong>, a series of 2-(3,4,5-trimethoxybenzoyl)quinazolin-4(3<em>H</em>)-one derivatives were synthesized and identified. Among them, CHNQD-01522 (<strong>18</strong>) exhibited the strongest cytotoxic activity against Huh-7 and HepG2 cell lines with IC₅₀ values of 0.19 and 0.17 μM. Meanwhile, treatment with CHNQD-01522 (<strong>18</strong>) suppressed tumor cell colony formation, arrested cell cycle in G2/M phases, and induced apoptosis. Mechanistic studies revealed that it is a novel microtubule inhibitor targeting the colchicine binding site, which cannot be transported by P-gp in cancer cells. Encouragingly, CHNQD-01522 (<strong>18</strong>) showed significant <em>in vivo</em> anti-tumor efficacy in the subcutaneous xenograft tumor model (TID, TGI = 79.09%) with frequency dependence. More importantly, the anti-tumor efficacy was also verified in an orthotopic xenograft tumor model. Furthermore, CHNQD-01522 (<strong>18</strong>) displayed satisfactory safety profiles in preliminary toxicity studies. Taken together, this study has identified a novel microtubule inhibitor with significant anti-hepatocellular carcinoma (HCC) activity, inherent resistance-avoidance property, and a favorable safety profile, showing promise as an HCC therapeutic.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118658"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of indolinone-based covalent ULK1 inhibitors that suppressed autophagy and induced apoptosis against colorectal carcinoma","authors":"Jing Ye ,&nbsp;Daihan Wang ,&nbsp;Haiying Pang ,&nbsp;Qiao Liu ,&nbsp;Zhaoping Pan ,&nbsp;Lian Wang ,&nbsp;Bo Liu ,&nbsp;Gu He","doi":"10.1016/j.ejmech.2026.118633","DOIUrl":"10.1016/j.ejmech.2026.118633","url":null,"abstract":"<div><div>Unc-51 Like Autophagy Activating Kinase 1 (ULK1) is an essential regulator in the initiation of autophagy and represents a novel therapeutic target for colorectal cancer (CRC) treatment. Herein, we developed a series of novel ULK1 covalent inhibitors through structure-based and medicinal chemistry optimizations. Notably, compound <strong>12i</strong> was synthesized and validated to form covalent bonds with ULK1, exhibiting pronounced selectivity and potent inhibitory activity (ULK1 IC₅₀ = 4.7 μM). Moreover, <strong>12i</strong> demonstrated anti-proliferative effects in CRC cell lines. <em>In vitro</em> experiments showed that <strong>12i</strong> effectively inhibited CRC cell growth, induced cell cycle arrest at the S or G2/M phase, and triggered apoptosis by blocking ULK1-mediated autophagy. Additionally, <em>in vivo</em> results showed that <strong>12i</strong> also exhibited good tumor inhibitory activity in CRC murine models, with an inhibition rate of 70.4 % at 40 mg/kg. <em>In vivo</em> pharmacokinetic studies revealed moderate systemic absorption (T_max = 2 h) with oral bioavailability of 39.7 % in rats. In summary, our findings highlight compound <strong>12i</strong> as a promising lead candidate for further development of selective ULK1 covalent inhibitors, offering a potential new strategy for CRC therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118633"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}