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Auristatin S: An Auristatin Payload with Improved Tolerability and Modified Bystander Activity. Auristatin S：一种具有改进耐受性和改进旁观者活动的Auristatin载荷。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-06-23 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00238
Philip N Moquist, Nicole M-L Eng-Duncan, Tim D Bovee, Katie Snead, Lauren Bou, Xinqun Zhang, Brittney Blackburn, Jennifer Wright, Jessica K Simmons, Haley D Neff-LaFord, Peter D Senter, Svetlana O Doronina
{"title":"Auristatin S: An Auristatin Payload with Improved Tolerability and Modified Bystander Activity.","authors":"Philip N Moquist, Nicole M-L Eng-Duncan, Tim D Bovee, Katie Snead, Lauren Bou, Xinqun Zhang, Brittney Blackburn, Jennifer Wright, Jessica K Simmons, Haley D Neff-LaFord, Peter D Senter, Svetlana O Doronina","doi":"10.1021/acsmedchemlett.5c00238","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00238","url":null,"abstract":"<p><p>Auristatins are a class of antibody-drug conjugate (ADC) payloads employed in anticancer therapies. Auristatin payloads are clinically validated and effective, but opportunities remain to improve their clinical benefit. Here, we describe the development and characterization of a new auristatin payload, Auristatin S, that demonstrates robust efficacy and improved off-target toxicity. This effort focused on the optimization of bystander activity, which is a key property that modulates the efficacy and tolerability of the ADC payloads. In vitro screening of tubulin binding, free drug cytotoxicity, and ADC activity were utilized to characterize the bystander activity profile. The corresponding peptide-linked conjugates showed excellent on-target cytotoxicity against cancer cells and induction of immunogenic cell death. Tolerability of Auristatin S was improved relative to historical controls, and in vivo activity and bystander activity were confirmed in a Karpas/KarpasBVR model.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1354-1358"},"PeriodicalIF":3.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Discovery of VNRX-9945, a Potent, Broadly Active Capsid Assembly Modulator as a Clinical Candidate for the Treatment of Chronic Hepatitis B Virus Infection. VNRX-9945，一种有效的，广泛活性的衣壳组装调节剂，作为慢性乙型肝炎病毒感染治疗的临床候选药物
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-06-20 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00315
Bin Liu, Jiangchao Yao, Thomas Haimowitz, Christopher A Benetatos, Steven A Boyd, Stephen M Condon, Christopher J Burns, Andre White, Damodharan Lakshminarasimhan, Robert K Suto, Ozgur Cakici, Anthony S Drager, Susan G Emeigh Hart, Daniel C Pevear, Glen A Coburn
{"title":"Discovery of VNRX-9945, a Potent, Broadly Active Capsid Assembly Modulator as a Clinical Candidate for the Treatment of Chronic Hepatitis B Virus Infection.","authors":"Bin Liu, Jiangchao Yao, Thomas Haimowitz, Christopher A Benetatos, Steven A Boyd, Stephen M Condon, Christopher J Burns, Andre White, Damodharan Lakshminarasimhan, Robert K Suto, Ozgur Cakici, Anthony S Drager, Susan G Emeigh Hart, Daniel C Pevear, Glen A Coburn","doi":"10.1021/acsmedchemlett.5c00315","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00315","url":null,"abstract":"<p><p>Targeting the capsid protein of the hepatitis B virus (HBV) has emerged as a promising strategy for developing new antiviral therapies. In this study, we report the discovery of a novel series of pyrrole oxo-carboxamide compounds as HBV capsid assembly modulators (CAMs) that block viral replication. Through a process of focused structure-activity relationship (SAR) optimization, we identified compound <b>12</b> (VNRX-9945), which exhibited excellent and broad antiviral activity against multiple HBV genotypes in vitro, along with favorable pharmacokinetic profiles across multiple species. Additionally, <b>12</b> demonstrated robust efficacy in the adeno-associated virus mouse model of HBV (AAV-HBV) infection. This compound has advanced into Phase 1 clinical trials to evaluate its safety and pharmacokinetics in healthy volunteers, to enable treatment of chronic HBV infections.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1209-1216"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Novel Indole Derivatives as Serotonergic Psychedelic Agents for Treating Psychosis, Mental Illness, and CNS Disorders. 新型吲哚衍生物作为5 -羟色胺能致幻剂用于治疗精神病、精神疾病和中枢神经系统障碍。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-06-20 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00362
Ram W Sabnis
{"title":"Novel Indole Derivatives as Serotonergic Psychedelic Agents for Treating Psychosis, Mental Illness, and CNS Disorders.","authors":"Ram W Sabnis","doi":"10.1021/acsmedchemlett.5c00362","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00362","url":null,"abstract":"<p><p>Provided herein are novel indole derivatives as serotonergic psychedelic agents, pharmaceutical compositions, use of such compounds in treating psychosis, mental illness and central nervous system (CNS) disorders, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1266-1267"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Selenium-Substituted BOIMPY for Enhanced Photodynamic Therapy. 硒取代BOIMPY增强光动力疗法。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-06-20 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00174
Sorachat Tharamak, Bongkot Ouengwanarat, Tunyawat Khrootkaew, Prapassara Muangsopa, Kantapat Chansaenpak, Kenika Khotchasanthong, Kittipong Chainok, Kevin Burgess, Anyanee Kamkaew
{"title":"Selenium-Substituted BOIMPY for Enhanced Photodynamic Therapy.","authors":"Sorachat Tharamak, Bongkot Ouengwanarat, Tunyawat Khrootkaew, Prapassara Muangsopa, Kantapat Chansaenpak, Kenika Khotchasanthong, Kittipong Chainok, Kevin Burgess, Anyanee Kamkaew","doi":"10.1021/acsmedchemlett.5c00174","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00174","url":null,"abstract":"<p><p>Seleno-substituted bis-(boron difluoride)-8-imidazo-dipyrro-methene (BOIMPY) derivatives displayed improved photophysical features over twisted-BOIMPY, such as greater Stokes shifts, while compromising radiative relaxation and intersystem crossing, making them suitable for imaging-guided photodynamic therapy (PDT). One exhibited improved Type I and Type II PDT against cancer cells when activated by near-infrared light. Its potential as a targeted PDT agent for cancer treatment is demonstrated by its remarkable phototoxicity in the nanomolar range and minimal dark toxicity.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1202-1208"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Advancing Isotope Labeling Technologies at AstraZeneca through Academic-Industrial Collaboration. 阿斯利康通过学术-工业合作推进同位素标记技术。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-06-20 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00338
Ryan A Bragg, Jonas Bergare, Markus Artelsmair, William J Kerr, Troels Skrydstrup, Charles S Elmore
{"title":"Advancing Isotope Labeling Technologies at AstraZeneca through Academic-Industrial Collaboration.","authors":"Ryan A Bragg, Jonas Bergare, Markus Artelsmair, William J Kerr, Troels Skrydstrup, Charles S Elmore","doi":"10.1021/acsmedchemlett.5c00338","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00338","url":null,"abstract":"<p><p>Academic-Industrial collaborations have played an important role in developing new synthetic methodologies for the isotope chemistry team at AstraZeneca. In this viewpoint, we present the outcome of two collaborations and illustrate how the innovative methodologies developed through these partnerships have been effectively applied within an AstraZeneca project.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1221-1225"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Novel Phenoxy and Benzyloxy Substituted Psychedelic Psychoplastogens as 5‑HT2C Agonists for Treating Neurological Diseases. 新型苯氧基和苯氧基取代致幻剂作为治疗神经系统疾病的5‑HT2C激动剂。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-06-19 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00363
Ram W Sabnis
{"title":"Novel Phenoxy and Benzyloxy Substituted Psychedelic Psychoplastogens as 5‑HT2C Agonists for Treating Neurological Diseases.","authors":"Ram W Sabnis","doi":"10.1021/acsmedchemlett.5c00363","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00363","url":null,"abstract":"<p><p>Provided herein are novel phenoxy and benzyloxy substituted psychedelic psychoplastogens as 5-HT2C agonists, pharmaceutical compositions, use of such compounds in treating neurological diseases, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1264-1265"},"PeriodicalIF":3.5,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Novel Heterocyclic 5H‑Dibenzo[b,f]azepine Derivatives as Selective HDAC6 Inhibitors for Treatment of Charcot Marie Tooth Disease. 新型杂环5H -二苯并[b，f]氮平衍生物作为选择性HDAC6抑制剂治疗夏可氏乳牙病。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-06-18 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00344
Steven H Liang
{"title":"Novel Heterocyclic 5<i>H</i>‑Dibenzo[b,f]azepine Derivatives as Selective HDAC6 Inhibitors for Treatment of Charcot Marie Tooth Disease.","authors":"Steven H Liang","doi":"10.1021/acsmedchemlett.5c00344","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00344","url":null,"abstract":"<p><p>This highlight describes novel substituted 5<i>H</i>-dibenzo-[b,f]-azepine compounds and their diverse biological applications. These compounds serve as selective inhibitors of histone deacetylase 6 (HDAC6), and provide methods for the treatment of a broad scope of indications, including Charcot Marie Tooth Disease (CMT).</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1245-1246"},"PeriodicalIF":3.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Novel (1H‑Pyrazol-4-ylamino)pyrimidine Derivatives as Wee1 Inhibitors for Treatment of Cancer. 新型（1H -吡唑-4-氨基）嘧啶衍生物作为Wee1抑制剂用于治疗癌症。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-06-18 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00343
Steven H Liang
{"title":"Novel (1<i>H</i>‑Pyrazol-4-ylamino)pyrimidine Derivatives as Wee1 Inhibitors for Treatment of Cancer.","authors":"Steven H Liang","doi":"10.1021/acsmedchemlett.5c00343","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00343","url":null,"abstract":"<p><p>This patent describes a series of novel (1<i>H</i>-pyrazol-4-ylamino)-pyrimidine derivatives, their salts or tautomer, and compositions and methods of preparation. These compounds are designed as selective Wee1 inhibitors for the treatment of cancer, including medulloblastoma and diffuse intrinsic pontine glioma (DlPG).</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1247-1248"},"PeriodicalIF":3.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Synthesis of Novel Substituted N‑Heterocycles and Their Use of Selective Poly(ADP-ribose) Polymerase 1 (PARP1) Inhibitors. 新型取代N -杂环的合成及其在选择性聚（adp -核糖）聚合酶1 （PARP1）抑制剂中的应用
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-06-18 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00340
Xin Zhou, Steven H Liang
{"title":"Synthesis of Novel Substituted <i>N</i>‑Heterocycles and Their Use of Selective Poly(ADP-ribose) Polymerase 1 (PARP1) Inhibitors.","authors":"Xin Zhou, Steven H Liang","doi":"10.1021/acsmedchemlett.5c00340","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00340","url":null,"abstract":"<p><p>Poly-(ADP-ribose) polymerase 1 (PARP1) is the most abundant and well-characterized member of the PARP family and plays a crucial role in gene expression, transcription, DNA damage response, and repair. This patent introduces the synthesis of substituted <i>N</i>-heterocycles and their applications in the treatment of PARP1-related diseases, such as cancer.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1254-1255"},"PeriodicalIF":3.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Novel Isoindolin-1-one Derivatives as Metabotropic Glutamate Receptor Positive Allosteric Modulators. 新型异吲哚-1- 1衍生物作为代谢性谷氨酸受体阳性变构调节剂。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-06-18 eCollection Date: 2025-07-10 DOI: 10.1021/acsmedchemlett.5c00342
Yinlong Li, Steven H Liang
{"title":"Novel Isoindolin-1-one Derivatives as Metabotropic Glutamate Receptor Positive Allosteric Modulators.","authors":"Yinlong Li, Steven H Liang","doi":"10.1021/acsmedchemlett.5c00342","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00342","url":null,"abstract":"<p><p>This highlight outlines the development of novel substituted isoindolin-1-one derivatives as potential positive allosteric modulators (PAMs) for group II metabotropic glutamate receptors (mGluR<sub>2</sub>/mGluR<sub>3</sub>). The disclosure includes details on synthetic methods, biological evaluation, and pharmaceutical compositions.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1249-1250"},"PeriodicalIF":3.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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