Pub Date : 2026-01-29DOI: 10.1021/acs.jmedchem.5c03655
Can Guo,Xiaolong Wang,Qianwen Guan,Sheng Zhong,Lu Zhang,Yimeng Liu,Bingjie Han,Jikuan Shao,Zongliang Liu,Yao Chen,Haopeng Sun
Osimertinib resistance driven by the cis-C797S/T790M EGFR triplet mutation remains clinically intractable. We identify aldo-keto reductase 1C3 (AKR1C3) as a metabolic vulnerability that sustains glutathione-reactive oxygen species (GSH-ROS) homeostasis in resistant non-small cell lung cancer (NSCLC). Starting from the selective inhibitor S07-2001, six rounds of structure-guided optimization delivered 55 analogues. The most advanced, SG-55, is a noncompetitive AKR1C3 inhibitor with nanomolar potency, exhibiting a half-maximal inhibitory concentration (IC50) of 5 ± 1 nM, whereas the IC50 values against AKR1C1, AKR1C2, and AKR1C4 are >10 μM. In 19Del/T790M/C797S mutant cells, SG-55 elevated the reduced/oxidized nicotinamide adenine dinucleotide phosphate (NADPH/NADP+) ratio, decreased the reduced/oxidized glutathione (GSH/GSSG) ratio, induced DNA double-strand breaks, and synergized with Osimertinib to suppress proliferation, clonogenicity, and survival. This combination therapy demonstrated efficacy in xenograft models and exhibited favorable pharmacokinetics in mice, thereby validating AKR1C3 blockade as a "metabolism-targeted" strategy to overcome resistance mediated by the EGFR C797S mutation.
{"title":"Discovery of Highly Selective AKR1C3 Inhibitors to Overcome EGFR C797S-Mediated Osimertinib Resistance in Non-Small Cell Lung Cancer.","authors":"Can Guo,Xiaolong Wang,Qianwen Guan,Sheng Zhong,Lu Zhang,Yimeng Liu,Bingjie Han,Jikuan Shao,Zongliang Liu,Yao Chen,Haopeng Sun","doi":"10.1021/acs.jmedchem.5c03655","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03655","url":null,"abstract":"Osimertinib resistance driven by the cis-C797S/T790M EGFR triplet mutation remains clinically intractable. We identify aldo-keto reductase 1C3 (AKR1C3) as a metabolic vulnerability that sustains glutathione-reactive oxygen species (GSH-ROS) homeostasis in resistant non-small cell lung cancer (NSCLC). Starting from the selective inhibitor S07-2001, six rounds of structure-guided optimization delivered 55 analogues. The most advanced, SG-55, is a noncompetitive AKR1C3 inhibitor with nanomolar potency, exhibiting a half-maximal inhibitory concentration (IC50) of 5 ± 1 nM, whereas the IC50 values against AKR1C1, AKR1C2, and AKR1C4 are >10 μM. In 19Del/T790M/C797S mutant cells, SG-55 elevated the reduced/oxidized nicotinamide adenine dinucleotide phosphate (NADPH/NADP+) ratio, decreased the reduced/oxidized glutathione (GSH/GSSG) ratio, induced DNA double-strand breaks, and synergized with Osimertinib to suppress proliferation, clonogenicity, and survival. This combination therapy demonstrated efficacy in xenograft models and exhibited favorable pharmacokinetics in mice, thereby validating AKR1C3 blockade as a \"metabolism-targeted\" strategy to overcome resistance mediated by the EGFR C797S mutation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"30 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1021/acs.jmedchem.5c02649
Jie Qiu,Shouwei Tao,Tian Zhang,Zhuang Miao,Shilong Hu,Wencheng Liu,Jianing Su,Ao Hai,Zhenbo Huang,Jin Liu,Dongxue Yang,Bowen Ke
Cyclooxygenase-2 (COX-2) and N-type voltage-gated calcium channels (CaV2.2) play pivotal roles in mediating inflammatory responses and regulating neuronal excitability in chronic pain. Concurrent modulation of these targets can achieve synergistic analgesic effects. We designed and synthesized a series of diarylpyrazole-based dual COX-2/CaV2.2 inhibitors. Structure-activity relationship analysis identified compound 5d as the lead candidate, exhibiting balanced inhibitory potency and favorable selectivity against COX-2 and CaV2.2, with IC50 values of 0.26 ± 0.17 μM and 0.29 ± 0.07 μM, respectively. In diverse models of inflammatory, neuropathic, and visceral pain, 5d produced pronounced analgesic effects. By simultaneously suppressing inflammatory responses and disrupting the stepwise amplification of nociceptive signaling, 5d embodies a multimechanistic analgesic strategy meriting further exploration.
{"title":"Design and Characterization of a Dual COX-2/CaV2.2 Inhibitor with Potent Analgesic Activity.","authors":"Jie Qiu,Shouwei Tao,Tian Zhang,Zhuang Miao,Shilong Hu,Wencheng Liu,Jianing Su,Ao Hai,Zhenbo Huang,Jin Liu,Dongxue Yang,Bowen Ke","doi":"10.1021/acs.jmedchem.5c02649","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02649","url":null,"abstract":"Cyclooxygenase-2 (COX-2) and N-type voltage-gated calcium channels (CaV2.2) play pivotal roles in mediating inflammatory responses and regulating neuronal excitability in chronic pain. Concurrent modulation of these targets can achieve synergistic analgesic effects. We designed and synthesized a series of diarylpyrazole-based dual COX-2/CaV2.2 inhibitors. Structure-activity relationship analysis identified compound 5d as the lead candidate, exhibiting balanced inhibitory potency and favorable selectivity against COX-2 and CaV2.2, with IC50 values of 0.26 ± 0.17 μM and 0.29 ± 0.07 μM, respectively. In diverse models of inflammatory, neuropathic, and visceral pain, 5d produced pronounced analgesic effects. By simultaneously suppressing inflammatory responses and disrupting the stepwise amplification of nociceptive signaling, 5d embodies a multimechanistic analgesic strategy meriting further exploration.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1021/acs.jmedchem.5c03424
Ahmed Elsheikh,Ganesh Bist,Sewon Kim,Ruea-Yea Huang,Donna Ruszaj,Devin Angevine,Amanda Duminuco,Youngjae You,Sukyung Woo
The apelin receptor (APJ) has emerged as a potential novel therapeutic target in cancer due to its role in regulating cell proliferation, angiogenesis, and metastasis. However, ML221, the only known selective small molecule APJ antagonist, exhibits poor plasma and liver microsomal stability, limiting its in vivo applicability. To overcome these limitations, a focused medicinal chemistry effort was undertaken to design and synthesize a second-generation series of APJ antagonists with improved metabolic stability while retaining APJ antagonist activity. Structure-activity relationship analysis identified compound 12 (YL-GB063) as the most favorable analog, displaying enhanced liver microsomal stability relative to lead compounds 6 (YL-GB053) and 7 (YL-GB054), while maintaining APJ inhibition. Pharmacokinetic evaluation revealed a >25-fold increase in systemic exposure compared to ML221. In an orthotopic ovarian cancer xenograft mouse model, YL-GB063 significantly increased median survival and reduced metastatic tumor burden and ascites formation compared to both control and ML221-treated groups.
{"title":"Design, Synthesis, and Pharmacological Evaluation of Metabolically Stable Apelin Receptor Antagonists with Improved In Vivo Exposure and Efficacy in Ovarian Cancer.","authors":"Ahmed Elsheikh,Ganesh Bist,Sewon Kim,Ruea-Yea Huang,Donna Ruszaj,Devin Angevine,Amanda Duminuco,Youngjae You,Sukyung Woo","doi":"10.1021/acs.jmedchem.5c03424","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03424","url":null,"abstract":"The apelin receptor (APJ) has emerged as a potential novel therapeutic target in cancer due to its role in regulating cell proliferation, angiogenesis, and metastasis. However, ML221, the only known selective small molecule APJ antagonist, exhibits poor plasma and liver microsomal stability, limiting its in vivo applicability. To overcome these limitations, a focused medicinal chemistry effort was undertaken to design and synthesize a second-generation series of APJ antagonists with improved metabolic stability while retaining APJ antagonist activity. Structure-activity relationship analysis identified compound 12 (YL-GB063) as the most favorable analog, displaying enhanced liver microsomal stability relative to lead compounds 6 (YL-GB053) and 7 (YL-GB054), while maintaining APJ inhibition. Pharmacokinetic evaluation revealed a >25-fold increase in systemic exposure compared to ML221. In an orthotopic ovarian cancer xenograft mouse model, YL-GB063 significantly increased median survival and reduced metastatic tumor burden and ascites formation compared to both control and ML221-treated groups.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"117 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1021/acs.jmedchem.5c03431
Yi He,Minghao Liu,Haohao Wang,Lu Han,Weiwei Han
Accurate prediction of drug-target binding affinity (DTA) remains a central challenge in drug discovery due to the need to integrate heterogeneous sequence, structural, and physicochemical information. Here, we propose PLMCA, a multimodal protein-ligand cross-attention framework that unifies protein sequence embeddings from two protein language models, three-dimensional geometric features, physicochemical descriptors, and ligand molecular graph representations within a single architecture. PLMCA further incorporates experimental assay conditions from the ChEMBL database as auxiliary inputs to mitigate batch effects and reduce measurement noise. On the PDBbind21 data set, PLMCA performs competitively or outperforms state-of-the-art methods under random, unseen-ligand, and unseen-protein splits for Kd and Ki prediction. On the ChEMBL_mini data set, PLMCA achieves R2 values of 0.531, 0.635, and 0.519 for IC50, Kd, and Ki prediction, respectively. In addition, PLMCA demonstrates robust protein binding pocket prediction performance, achieving an AUPR of up to 0.655 under the unseen-protein setting.
{"title":"PLMCA: A General Multimodal Protein-Ligand Cross-Attention Framework for Pocket Identification and Binding Affinity Prediction.","authors":"Yi He,Minghao Liu,Haohao Wang,Lu Han,Weiwei Han","doi":"10.1021/acs.jmedchem.5c03431","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03431","url":null,"abstract":"Accurate prediction of drug-target binding affinity (DTA) remains a central challenge in drug discovery due to the need to integrate heterogeneous sequence, structural, and physicochemical information. Here, we propose PLMCA, a multimodal protein-ligand cross-attention framework that unifies protein sequence embeddings from two protein language models, three-dimensional geometric features, physicochemical descriptors, and ligand molecular graph representations within a single architecture. PLMCA further incorporates experimental assay conditions from the ChEMBL database as auxiliary inputs to mitigate batch effects and reduce measurement noise. On the PDBbind21 data set, PLMCA performs competitively or outperforms state-of-the-art methods under random, unseen-ligand, and unseen-protein splits for Kd and Ki prediction. On the ChEMBL_mini data set, PLMCA achieves R2 values of 0.531, 0.635, and 0.519 for IC50, Kd, and Ki prediction, respectively. In addition, PLMCA demonstrates robust protein binding pocket prediction performance, achieving an AUPR of up to 0.655 under the unseen-protein setting.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"8 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Immunoglobulin G (IgG) is a multifunctional glycoprotein essential for immune defense and widely used as a therapeutic due to its antigen specificity and effector functions. However, the inherent flexibility of its hinge region complicates structural characterization and obscures the molecular basis of its mechanism of action. To clarify the hinge’s role, we performed systematic amino acid substitutions. Notably, deletion of Pro230 led to the formation of a half-IgG1 species lacking inter-heavy chain interactions. Structural analysis using nuclear magnetic resonance (NMR), negative-stain EM, and disulfide bond quantification by LC-MS/MS peptide mapping revealed the mechanism underlying half-IgG1 generation. To enable this, we developed a new stable-isotope labeling method for NMR. Functional assays with FcγR-expressing reporter cells demonstrated that half-IgG1 retained selective FcγRI-mediated activity. These findings provide new insights into higher-order IgG structure and Fcγ receptor-dependent immune activation, offering a basis for designing next-generation antibody therapeutics.
免疫球蛋白G （IgG）是一种免疫防御必需的多功能糖蛋白，因其抗原特异性和效应功能而广泛应用于治疗。然而，其铰链区域固有的柔韧性使其结构表征复杂化，并使其作用机制的分子基础模糊不清。为了阐明铰链的作用，我们进行了系统的氨基酸替换。值得注意的是，Pro230的缺失导致了缺乏重链间相互作用的半igg1物种的形成。利用核磁共振（NMR）、阴性染色EM和LC-MS/MS肽图谱的二硫键定量分析揭示了半igg1产生的机制。为了实现这一点，我们开发了一种新的核磁共振稳定同位素标记方法。用表达fc γ r的报告细胞进行的功能分析表明，一半的igg1保留了选择性的fc γ r -介导活性。这些发现为高阶IgG结构和Fcγ受体依赖性免疫激活提供了新的见解，为设计下一代抗体疗法提供了基础。
{"title":"Key Role of Pro230 in the Hinge Region on the Architecture and Function of IgG1","authors":"Yuuki Koseki, Yuki Yamaguchi, Michihiko Aoyama, Kentaro Hiraka, Minoru Tada, Atsuji Kodama, Akinobu Senoo, Akiko Ishii-Watabe, Takayuki Uchihashi, Kazuyoshi Murata, Susumu Uchiyama, Koichi Kato, Saeko Yanaka, Jose M.M. Caaveiro","doi":"10.1021/acs.jmedchem.5c02419","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02419","url":null,"abstract":"Immunoglobulin G (IgG) is a multifunctional glycoprotein essential for immune defense and widely used as a therapeutic due to its antigen specificity and effector functions. However, the inherent flexibility of its hinge region complicates structural characterization and obscures the molecular basis of its mechanism of action. To clarify the hinge’s role, we performed systematic amino acid substitutions. Notably, deletion of Pro230 led to the formation of a half-IgG1 species lacking inter-heavy chain interactions. Structural analysis using nuclear magnetic resonance (NMR), negative-stain EM, and disulfide bond quantification by LC-MS/MS peptide mapping revealed the mechanism underlying half-IgG1 generation. To enable this, we developed a new stable-isotope labeling method for NMR. Functional assays with FcγR-expressing reporter cells demonstrated that half-IgG1 retained selective FcγRI-mediated activity. These findings provide new insights into higher-order IgG structure and Fcγ receptor-dependent immune activation, offering a basis for designing next-generation antibody therapeutics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146070649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1021/acs.jmedchem.6c00067
Craig Lindsley, Deepak B. Salunke, Rahul Kumar
Figure 1. Chemical structures of lead compounds targeting TLR2/1. Figure 2. Lead compounds targeting TLR4. Figure 3. Recently reported imidazo[4,5-c]quinoline based TLR7/8 agonists. Figure 4. Lead compounds targeting TLR7/8. Figure 5. Chemical structures of lead compounds targeting mincle receptor. Figure 6. Lead chemical structures identified via novel adjuvant discovery approaches. Figure 7. Lead compounds targeting miscellaneous pathways for vaccine adjuvant discovery. Figure 8. Chemical structure of αGC-SS-IMDQ-Ac. Figure 9. Pam3CSK4–BSA-MUC1 conjugate (57). Figure 10. Chemical structures of FP20 (58) and QS-21 (59). Figure 11. QS-21 derivatives 60, 61, and 62. This work was supported by the funds from the Centre of Excellence (CoE AB-AV) under the Scheme for the Promotion of Research and Innovation in Pharma MedTech (PRIP) by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India, at NIPER Mohali. R.K. thanks the Anusandhan National Research Foundation (ANRF)-NPDF, New Delhi-110016, for the financial support (PDF/2023/002964). This article references 28 other publications. This article has not yet been cited by other publications.
{"title":"Medicinal Chemistry of Next Generation Vaccine Adjuvants","authors":"Craig Lindsley, Deepak B. Salunke, Rahul Kumar","doi":"10.1021/acs.jmedchem.6c00067","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c00067","url":null,"abstract":"Figure 1. Chemical structures of lead compounds targeting TLR2/1. Figure 2. Lead compounds targeting TLR4. Figure 3. Recently reported imidazo[4,5-<i>c</i>]quinoline based TLR7/8 agonists. Figure 4. Lead compounds targeting TLR7/8. Figure 5. Chemical structures of lead compounds targeting mincle receptor. Figure 6. Lead chemical structures identified via novel adjuvant discovery approaches. Figure 7. Lead compounds targeting miscellaneous pathways for vaccine adjuvant discovery. Figure 8. Chemical structure of αGC-SS-IMDQ-Ac. Figure 9. Pam<sub>3</sub>CSK<sub>4</sub>–BSA-MUC1 conjugate (<b>57</b>). Figure 10. Chemical structures of FP20 (<b>58</b>) and QS-21 (<b>59</b>). Figure 11. QS-21 derivatives <b>60</b>, <b>61</b>, and <b>62</b>. This work was supported by the funds from the Centre of Excellence (CoE AB-AV) under the Scheme for the Promotion of Research and Innovation in Pharma MedTech (PRIP) by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India, at NIPER Mohali. R.K. thanks the Anusandhan National Research Foundation (ANRF)-NPDF, New Delhi-110016, for the financial support (PDF/2023/002964). This article references 28 other publications. This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146070666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1021/acs.jmedchem.5c03138
James S Scott, Laura Evans, Peter C Astles, Argyrides Argyrou, Sharan K Bagal, David Beattie, Erin L Braybrooke, Doyle J Cassar, Claire Crafter, Coura Diène, Gary Fairley, Charlene Fallan, Graham Fraser, Nuria Galeano-Dalmau, Thomas G Hammond, Andreas K Hock, Thomas Jones, Jasper Komen, Gillian M Lamont, Chrysiis Michaloglou, Michael J Niedbala, Antonio Ramos-Montoya, Monica C Rodrigo-Brenni, Martin J Packer, Stuart Pearson, Andy Pike, Markus Schade, Joseph Shaw, Ziyanda Shologu, Oliver Steward
Androgen Receptor (AR) signaling plays a pivotal role in the development and progression of prostate cancer. Herein, we describe the discovery and optimization of a novel series of AR PROTACs capable of degrading AR and important resistance mutations such as L702H AR. A novel AR-binding cyanoindole motif was identified from a directed screen of the AstraZeneca collection. This was optimized and elaborated to identify a suitable exit vector from which to form an initial PROTAC capable of degrading AR. The series was further optimized in terms of potency and rodent oral bioavailability with an isomeric switch of the piperidine substitution, removing an in vitro mitotoxicity signal to give 3n. This compound inhibited AR signaling in vitro and was able to inhibit tumor growth in vivo in a mouse prostate cancer xenograft model. Extensive profiling in terms of drug-like properties allowed this to be progressed into development as AZD9750.
{"title":"Discovery of AZD9750, an Orally Bioavailable Androgen Receptor Degrader for the Treatment of Prostate Cancer.","authors":"James S Scott, Laura Evans, Peter C Astles, Argyrides Argyrou, Sharan K Bagal, David Beattie, Erin L Braybrooke, Doyle J Cassar, Claire Crafter, Coura Diène, Gary Fairley, Charlene Fallan, Graham Fraser, Nuria Galeano-Dalmau, Thomas G Hammond, Andreas K Hock, Thomas Jones, Jasper Komen, Gillian M Lamont, Chrysiis Michaloglou, Michael J Niedbala, Antonio Ramos-Montoya, Monica C Rodrigo-Brenni, Martin J Packer, Stuart Pearson, Andy Pike, Markus Schade, Joseph Shaw, Ziyanda Shologu, Oliver Steward","doi":"10.1021/acs.jmedchem.5c03138","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03138","url":null,"abstract":"<p><p>Androgen Receptor (AR) signaling plays a pivotal role in the development and progression of prostate cancer. Herein, we describe the discovery and optimization of a novel series of AR PROTACs capable of degrading AR and important resistance mutations such as L702H AR. A novel AR-binding cyanoindole motif was identified from a directed screen of the AstraZeneca collection. This was optimized and elaborated to identify a suitable exit vector from which to form an initial PROTAC capable of degrading AR. The series was further optimized in terms of potency and rodent oral bioavailability with an isomeric switch of the piperidine substitution, removing an <i>in vitro</i> mitotoxicity signal to give <b>3n</b>. This compound inhibited AR signaling <i>in vitro</i> and was able to inhibit tumor growth <i>in vivo</i> in a mouse prostate cancer xenograft model. Extensive profiling in terms of drug-like properties allowed this to be progressed into development as AZD9750.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Polθ, a key enzyme mediating microhomology-mediated end joining (MMEJ), is overexpressed in multiple human cancers and represents a promising therapeutic target, particularly in tumors with homologous recombination (HR) deficiency. Herein, we report the discovery and optimization of a novel series of Polθ polymerase (Polθ-pol) inhibitors featuring an arylalkyne scaffold, which extends into a peripheral channel within the polymerase domain to enhance target engagement. Among the synthesized compounds, compound 20 exhibited potent inhibitory activity against Polθ-pol at a nanomolar level (IC50 = 1.3 nM), along with antiproliferative activity against the HR-deficient cancer cell lines, such as MDA-MB-436, Capan-1, and DLD-1 (BRCA2-/-). Moreover, compound 20 demonstrated favorable pharmacokinetic properties, with oral bioavailability values of 103.36% in mice and 63.71% in rats, respectively. In an MDA-MB-436 xenograft model, compound 20 significantly suppressed tumor growth without evident toxicity. These findings underscore the arylalkyne scaffold as a highly promising strategy for the development of orally active Polθ-targeted therapeutics.
{"title":"Discovery of Novel Orally Bioavailable Polθ Inhibitors with Arylalkyne Scaffolds for Targeting HR-Deficient Cancers.","authors":"Jinyang Zhang,Xiaomeng Sun,Qichen Zhou,Yingying Wei,Biao Chen,Junhui Jiao,Yu Du,Shepherd Wufoyrwoth,Haoze Chi,Yi Yang,Ping Wei,Yungen Xu,Yi Zou,Qihua Zhu","doi":"10.1021/acs.jmedchem.5c01977","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01977","url":null,"abstract":"Polθ, a key enzyme mediating microhomology-mediated end joining (MMEJ), is overexpressed in multiple human cancers and represents a promising therapeutic target, particularly in tumors with homologous recombination (HR) deficiency. Herein, we report the discovery and optimization of a novel series of Polθ polymerase (Polθ-pol) inhibitors featuring an arylalkyne scaffold, which extends into a peripheral channel within the polymerase domain to enhance target engagement. Among the synthesized compounds, compound 20 exhibited potent inhibitory activity against Polθ-pol at a nanomolar level (IC50 = 1.3 nM), along with antiproliferative activity against the HR-deficient cancer cell lines, such as MDA-MB-436, Capan-1, and DLD-1 (BRCA2-/-). Moreover, compound 20 demonstrated favorable pharmacokinetic properties, with oral bioavailability values of 103.36% in mice and 63.71% in rats, respectively. In an MDA-MB-436 xenograft model, compound 20 significantly suppressed tumor growth without evident toxicity. These findings underscore the arylalkyne scaffold as a highly promising strategy for the development of orally active Polθ-targeted therapeutics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"52 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1021/acs.jmedchem.5c03032
Rensong Sun, Zhihao Chen, Ruitao Yang, Yuan Liang, Wen Sun, Engin U. Akkaya, Lei Wang
Tumor microenvironment not only compromises the therapeutic efficacy of chemotherapy but also weakens chemotherapy-induced immunogenic cell death. Herein, we report novel platinumIV prodrugs that integrate two clinically approved drugs with different but complementary mechanisms, where cisplatin provides tumor cytotoxicity while the pirfenidone analogue contributes to tumor microenvironment modulation. In vitro evaluations suggested their superior anticancer activity, improved resistance profiles, and favorable selectivity across multiple cancer cell lines. Mechanistic studies revealed that they not only depleted intracellular glutathione and suppressed P-gp expression but also remodeled the tumor microenvironment through multiple actions. Notably, they triggered the release of damage-associated molecular patterns (DAMPs), promoted dendritic cell maturation, and induced strong immunogenic cell death despite that cisplatin is unable to induce an immunological response. In vivo studies further confirmed their antitumor activity (3.3-fold tumor inhibition compared to cisplatin) and favorable safety profile (64% weight loss by cisplatin, none with platinumIV complexes).
{"title":"PlatinumIV Complex Enabling Multiple and Potent Tumor Microenvironment Remodeling for Cancer Chemo-Immunotherapy","authors":"Rensong Sun, Zhihao Chen, Ruitao Yang, Yuan Liang, Wen Sun, Engin U. Akkaya, Lei Wang","doi":"10.1021/acs.jmedchem.5c03032","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03032","url":null,"abstract":"Tumor microenvironment not only compromises the therapeutic efficacy of chemotherapy but also weakens chemotherapy-induced immunogenic cell death. Herein, we report novel platinum<sup>IV</sup> prodrugs that integrate two clinically approved drugs with different but complementary mechanisms, where cisplatin provides tumor cytotoxicity while the pirfenidone analogue contributes to tumor microenvironment modulation. In vitro evaluations suggested their superior anticancer activity, improved resistance profiles, and favorable selectivity across multiple cancer cell lines. Mechanistic studies revealed that they not only depleted intracellular glutathione and suppressed P-gp expression but also remodeled the tumor microenvironment through multiple actions. Notably, they triggered the release of damage-associated molecular patterns (DAMPs), promoted dendritic cell maturation, and induced strong immunogenic cell death despite that cisplatin is unable to induce an immunological response. In vivo studies further confirmed their antitumor activity (3.3-fold tumor inhibition compared to cisplatin) and favorable safety profile (64% weight loss by cisplatin, none with platinum<sup>IV</sup> complexes).","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146070668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1021/acs.jmedchem.5c01426
Adi Suwandi,Jianwen Jin,Yichao Zhao,Ramesh Mudududdla,Yi Sing Gee,Girdhar Singh Deora,Yuxin Sun,Heping Wei,Fei Huang,Jin-Shu He,Amee J George,Stefan J Hermans,David J Leaver,Michael W Parker,Jonathan B Baell
All lysine acetyltransferases (KATs) modulate biological outcomes through the acetylation of lysine side-chain amino groups facilitated by acetyl coenzyme A (AcCoA). KAT6A belongs to the class of MYST domain histone acetyltransferases (HATs), which had been regarded as undruggable. The first on-target KAT6A inhibitors with in vivo activity were reported in 2018, catalyzing intense industry interest in this enzyme as an oncology target. In this study, we experimentally evaluated representative KAT6A inhibitor chemotypes through resynthesis and comparative biochemical assays, cellular assays, and structural biology. We outline the recent history of each KAT6A inhibitor chemotype discovery, including SAR for potency, selectivity, and cellular activity. We extensively benchmark key compounds from each chemotype, augmented by new acylsulfonohydrazide analogues and a novel fused [1,2,4]thiadiazine KAT6A inhibitor subclass, which we report here for the first time, along with co-crystal structures. Additionally, we report on the in vivo activity, pharmacokinetics, and toxicology profiles of these inhibitors.
{"title":"Biological Activity and Structural Biology of Current KAT6A Inhibitor Chemotypes.","authors":"Adi Suwandi,Jianwen Jin,Yichao Zhao,Ramesh Mudududdla,Yi Sing Gee,Girdhar Singh Deora,Yuxin Sun,Heping Wei,Fei Huang,Jin-Shu He,Amee J George,Stefan J Hermans,David J Leaver,Michael W Parker,Jonathan B Baell","doi":"10.1021/acs.jmedchem.5c01426","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01426","url":null,"abstract":"All lysine acetyltransferases (KATs) modulate biological outcomes through the acetylation of lysine side-chain amino groups facilitated by acetyl coenzyme A (AcCoA). KAT6A belongs to the class of MYST domain histone acetyltransferases (HATs), which had been regarded as undruggable. The first on-target KAT6A inhibitors with in vivo activity were reported in 2018, catalyzing intense industry interest in this enzyme as an oncology target. In this study, we experimentally evaluated representative KAT6A inhibitor chemotypes through resynthesis and comparative biochemical assays, cellular assays, and structural biology. We outline the recent history of each KAT6A inhibitor chemotype discovery, including SAR for potency, selectivity, and cellular activity. We extensively benchmark key compounds from each chemotype, augmented by new acylsulfonohydrazide analogues and a novel fused [1,2,4]thiadiazine KAT6A inhibitor subclass, which we report here for the first time, along with co-crystal structures. Additionally, we report on the in vivo activity, pharmacokinetics, and toxicology profiles of these inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"42 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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