Pub Date : 2026-04-01Epub Date: 2026-01-10DOI: 10.1016/j.bmc.2026.118552
Feifei Wang , Hongxue Dai , Kuanxin Wan , Mingliang Wang
CDK12 (Cyclin-dependent kinase 12) is a cyclin-dependent kinase that regulates gene transcription by phosphorylating the C-terminal domain of RNA polymerase II, playing a crucial role in maintaining genomic stability. Mutations or alterations in the CDK12 genome can trigger tumorigenesis and progression. Inhibiting the overexpression of CDK12 suppresses tumor growth and proliferation, indicating that it serves both as a biomarker for tumorigenesis and a potential therapeutic target for cancer treatment. In recent years, the structure and biological functions of CDK12 have been progressively elucidated, attracting significant research attention. Currently, the CDK12/13 inhibitor CT7439 is undergoing Phase I/II clinical trials. This paper provides a detailed review of various types of CDK12 small-molecule inhibitors/degraders, primarily based on key structural frameworks. It focuses on exploring the existing structure-activity relationships, aiming to offer a comprehensive perspective for developing highly selective CDK12-targeted inhibitors/degraders and providing valuable insights for future novel drug development.
{"title":"Therapeutic targeting of CDK12: a medicinal chemistry perspective","authors":"Feifei Wang , Hongxue Dai , Kuanxin Wan , Mingliang Wang","doi":"10.1016/j.bmc.2026.118552","DOIUrl":"10.1016/j.bmc.2026.118552","url":null,"abstract":"<div><div>CDK12 (Cyclin-dependent kinase 12) is a cyclin-dependent kinase that regulates gene transcription by phosphorylating the C-terminal domain of RNA polymerase II, playing a crucial role in maintaining genomic stability. Mutations or alterations in the CDK12 genome can trigger tumorigenesis and progression. Inhibiting the overexpression of CDK12 suppresses tumor growth and proliferation, indicating that it serves both as a biomarker for tumorigenesis and a potential therapeutic target for cancer treatment. In recent years, the structure and biological functions of CDK12 have been progressively elucidated, attracting significant research attention. Currently, the CDK12/13 inhibitor CT7439 is undergoing Phase I/II clinical trials. This paper provides a detailed review of various types of CDK12 small-molecule inhibitors/degraders, primarily based on key structural frameworks. It focuses on exploring the existing structure-activity relationships, aiming to offer a comprehensive perspective for developing highly selective CDK12-targeted inhibitors/degraders and providing valuable insights for future novel drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118552"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2026-01-12DOI: 10.1016/j.bmc.2026.118555
Anastasiya S. Sokolova , Valeria V. Samsonova , Sergey O. Kuranov , Оlga I. Yarovaya , Artem D. Rogachev , Iana L. Esaulkova , Alexandrina S. Volobueva , Vladimir V. Zarubaev , Nariman F. Salakhutdinov
The persistent threat of influenza pandemics and the limitations of existing therapies necessitate the discovery of novel antiviral agents. This study investigates a series of monoterpenoid-based benzamides, derived from natural products (+)-camphor and (−)-fenchone, as a new class of inhibitors against influenza A virus (IAV). Building upon previous findings of their activity against orthopoxviruses, we identified several derivatives with potent activity against the A/H1N1 strain. Structure-activity relationship (SAR) analysis revealed that antiviral efficacy is critically dependent on the substituent's nature and position on the aromatic ring, the stereochemistry of the bicyclo[2.2.1]heptane core, and the amide configuration. Key lead compounds demonstrated significant inhibitory activity against the A/Puerto Rico/8/34 (H1N1) strain with high selectivity, and one derivative also showed promising activity against the highly pathogenic A(H7N9) strain. A representative compound demonstrated high metabolic stability in murine blood in vitro and exhibited promising pharmacokinetic properties in vivo following intragastric administration in mice. Mechanistic studies revealed two distinct profiles: one subset of inhibitors likely targets viral entry, while another appears to interfere with a later stage, such as assembly; their action is not mediated by neuraminidase inhibition. These findings establish monoterpenoid benzamides bearing the bicyclo[2.2.1]heptane motif as a promising scaffold for the development of anti-influenza agents, warranting further investigation into their precise molecular target and in vivo efficacy.
{"title":"Discovery of monoterpenoid-based benzamides bearing bicyclo[2.2.1]heptane motif as influenza H1N1 virus inhibitors","authors":"Anastasiya S. Sokolova , Valeria V. Samsonova , Sergey O. Kuranov , Оlga I. Yarovaya , Artem D. Rogachev , Iana L. Esaulkova , Alexandrina S. Volobueva , Vladimir V. Zarubaev , Nariman F. Salakhutdinov","doi":"10.1016/j.bmc.2026.118555","DOIUrl":"10.1016/j.bmc.2026.118555","url":null,"abstract":"<div><div>The persistent threat of influenza pandemics and the limitations of existing therapies necessitate the discovery of novel antiviral agents. This study investigates a series of monoterpenoid-based benzamides, derived from natural products (+)-camphor and (−)-fenchone, as a new class of inhibitors against influenza A virus (IAV). Building upon previous findings of their activity against orthopoxviruses, we identified several derivatives with potent activity against the A/H1N1 strain. Structure-activity relationship (SAR) analysis revealed that antiviral efficacy is critically dependent on the substituent's nature and position on the aromatic ring, the stereochemistry of the bicyclo[2.2.1]heptane core, and the amide configuration. Key lead compounds demonstrated significant inhibitory activity against the A/Puerto Rico/8/34 (H1N1) strain with high selectivity, and one derivative also showed promising activity against the highly pathogenic A(H7N9) strain. A representative compound demonstrated high metabolic stability in murine blood in vitro and exhibited promising pharmacokinetic properties in vivo following intragastric administration in mice. Mechanistic studies revealed two distinct profiles: one subset of inhibitors likely targets viral entry, while another appears to interfere with a later stage, such as assembly; their action is not mediated by neuraminidase inhibition. These findings establish monoterpenoid benzamides bearing the bicyclo[2.2.1]heptane motif as a promising scaffold for the development of anti-influenza agents, warranting further investigation into their precise molecular target and in vivo efficacy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118555"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2026-01-31DOI: 10.1016/j.bmc.2026.118582
Yazhou Wang , Xiaomin Wang , Chao Wang , Tingting Liu , Xin Cai , Man Zhang , Alex Aliper , Feng Ren , Alex Zhavoronkov , Xiao Ding
Through structure-based design to optimize protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) inhibitors, we developed two distinct conformational restriction strategies: intermolecular hydrogen bonding and cyclization. The hinge-binding carboxamide cyclized derivative B3 demonstrated potent enzymatic inhibition (IC50 = 3.5 nM) and cellular CDK1 phosphorylation suppression (IC50 = 65–114 nM), selectively inhibited proliferation of CCNE1-amplified cancer cells (IC50 = 0.56–0.88 μM) through induction of γH2AX accumulation. Furthermore, compared to the first-in-class PKMYT1 inhibitor RP-6306, B3 exhibited enhanced solubility (176 vs 45 μM) and favorable in vivo metabolic stability (mouse clearance 58.2 vs 85.7 mL/min/kg), underscoring cyclization as a productive design strategy to improve drug-likeness of PKMYT1 inhibitors.
{"title":"Conformational restriction of hinge carboxamide leading to potent lactam-based PKMYT1 inhibitors","authors":"Yazhou Wang , Xiaomin Wang , Chao Wang , Tingting Liu , Xin Cai , Man Zhang , Alex Aliper , Feng Ren , Alex Zhavoronkov , Xiao Ding","doi":"10.1016/j.bmc.2026.118582","DOIUrl":"10.1016/j.bmc.2026.118582","url":null,"abstract":"<div><div>Through structure-based design to optimize protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) inhibitors, we developed two distinct conformational restriction strategies: intermolecular hydrogen bonding and cyclization. The hinge-binding carboxamide cyclized derivative <strong>B3</strong> demonstrated potent enzymatic inhibition (IC<sub>50</sub> = 3.5 nM) and cellular CDK1 phosphorylation suppression (IC<sub>50</sub> = 65–114 nM), selectively inhibited proliferation of <em>CCNE1</em>-amplified cancer cells (IC<sub>50</sub> = 0.56–0.88 μM) through induction of γH2AX accumulation. Furthermore, compared to the first-in-class PKMYT1 inhibitor RP-6306, <strong>B3</strong> exhibited enhanced solubility (176 <em>vs</em> 45 μM) and favorable <em>in vivo</em> metabolic stability (mouse clearance 58.2 <em>vs</em> 85.7 mL/min/kg), underscoring cyclization as a productive design strategy to improve drug-likeness of PKMYT1 inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118582"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2026-01-05DOI: 10.1016/j.bmc.2026.118548
Xiaofeng Chen, Enyuan Zhang, Pan Wang, Lifeng Ning
Poly (ADP-ribose) polymerase-1 (PARP-1) is a key DNA repair enzyme targeted in cancer therapy. We developed an AI-assisted virtual screening workflow combining RG-MPNN for shape-based screening and PIGNet for docking rescoring to identify novel PARP1 inhibitors from an 18-million compound library. Five hits showed nanomolar activity, with Hit 1 exhibiting 8.03 nM IC₅₀ and a novel tricyclic scaffold. Comprehensive validation confirmed PARP1 inhibition, selective cytotoxicity in BRCA1-deficient cells, and favorable drug-like properties. Hit 1 represents a promising candidate for further development.
{"title":"AI-aided virtual screening and biological evaluation for discovering new potential poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors","authors":"Xiaofeng Chen, Enyuan Zhang, Pan Wang, Lifeng Ning","doi":"10.1016/j.bmc.2026.118548","DOIUrl":"10.1016/j.bmc.2026.118548","url":null,"abstract":"<div><div>Poly (ADP-ribose) polymerase-1 (PARP-1) is a key DNA repair enzyme targeted in cancer therapy. We developed an AI-assisted virtual screening workflow combining RG-MPNN for shape-based screening and PIGNet for docking rescoring to identify novel PARP1 inhibitors from an 18-million compound library. Five hits showed nanomolar activity, with Hit 1 exhibiting 8.03 nM IC₅₀ and a novel tricyclic scaffold. Comprehensive validation confirmed PARP1 inhibition, selective cytotoxicity in BRCA1-deficient cells, and favorable drug-like properties. Hit 1 represents a promising candidate for further development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118548"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2026-01-27DOI: 10.1016/j.bmc.2026.118575
Iain D.G. Watson , Justin A. Morin , Pandiaraju R. Subramanian , Anh M. Chau , Michael A. Prakesch , Brian J. Wilson , Monzur M. Morshed , Babu B. Joseph , David E. Uehling , Gennady Poda , Ayome Abibi , Manuel Chan , Herman Cheung , Carly Griffin , Victor Mao , Richard Marcellus , Craig Strathdee , Ratheesh Subramaniam , Brigitte L. Thériault , Jeffrey Winston , Methvin B. Isaac
B-cell lymphoma 6 (BCL6) is a transcriptional repressor protein central to the development and maintenance of germinal centers (GCs) during the humoral immune response. BCL6 is often deregulated in diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin's lymphoma, and inhibition of the protein−protein interaction between BCL6 and corepressors has been implicated as a therapeutic strategy. Based on a previously identified small molecule binding site on the BCL6 BTB domain, we carried out a virtual screen and identified a set of high micromolar screening hits. One series was advanced to a low micromolar confirmed hit via iterative rounds of compound optimization guided by structure activity relationships and co-crystal structures. Overall, we were able to use a rational, structure-based drug design approach to identify and advance a novel series of pyrrolopyrimidinone BCL6 BTB inhibitors.
{"title":"Discovery of pyrrolopyrimidinone inhibitors of the BCL6-SMRT corepressor interaction","authors":"Iain D.G. Watson , Justin A. Morin , Pandiaraju R. Subramanian , Anh M. Chau , Michael A. Prakesch , Brian J. Wilson , Monzur M. Morshed , Babu B. Joseph , David E. Uehling , Gennady Poda , Ayome Abibi , Manuel Chan , Herman Cheung , Carly Griffin , Victor Mao , Richard Marcellus , Craig Strathdee , Ratheesh Subramaniam , Brigitte L. Thériault , Jeffrey Winston , Methvin B. Isaac","doi":"10.1016/j.bmc.2026.118575","DOIUrl":"10.1016/j.bmc.2026.118575","url":null,"abstract":"<div><div>B-cell lymphoma 6 (BCL6) is a transcriptional repressor protein central to the development and maintenance of germinal centers (GCs) during the humoral immune response. BCL6 is often deregulated in diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin's lymphoma, and inhibition of the protein−protein interaction between BCL6 and corepressors has been implicated as a therapeutic strategy. Based on a previously identified small molecule binding site on the BCL6 BTB domain, we carried out a virtual screen and identified a set of high micromolar screening hits. One series was advanced to a low micromolar confirmed hit via iterative rounds of compound optimization guided by structure activity relationships and co-crystal structures. Overall, we were able to use a rational, structure-based drug design approach to identify and advance a novel series of pyrrolopyrimidinone BCL6 BTB inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118575"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2026-01-30DOI: 10.1016/j.bmc.2026.118579
Hong-Anh Pham , Quoc-Gia Mai , Thuan-Thien Dinh , Byeol-Hee Cho , Manh-Liem Le , Kien-Quang Huynh , Yong-Suk Jang , Hieu Tran-Van
Here, we report the structure-guided identification pipeline of a novel PrPC-binding peptide, PEP1, derived from Brucella abortus Hsp60 through computational docking. Computational modeling predicted that PEP1 engages the PrPC binding interface with favorable binding energetics, motivating its experimental evaluation as a receptor-targeting ligand. Fusion of PEP1 to a model protein enabled receptor-mediated targeting to intestinal M-cell-associated regions and resulted in increased mucosal IgA and systemic IgG responses relative to the untargeted protein. Together, these findings establish PEP1 as a minimal peptide ligand that promotes receptor-mediated antigen uptake through M cells, demonstrating the utility of structure-guided approaches for discovering functional targeting peptides.
{"title":"Structure-guided identification of a PrPC-binding peptide derived from Brucella abortus Hsp60 for receptor-mediated mucosal targeting","authors":"Hong-Anh Pham , Quoc-Gia Mai , Thuan-Thien Dinh , Byeol-Hee Cho , Manh-Liem Le , Kien-Quang Huynh , Yong-Suk Jang , Hieu Tran-Van","doi":"10.1016/j.bmc.2026.118579","DOIUrl":"10.1016/j.bmc.2026.118579","url":null,"abstract":"<div><div>Here, we report the structure-guided identification pipeline of a novel PrP<sup>C</sup>-binding peptide, PEP1, derived from <em>Brucella abortus</em> Hsp60 through computational docking. Computational modeling predicted that PEP1 engages the PrP<sup>C</sup> binding interface with favorable binding energetics, motivating its experimental evaluation as a receptor-targeting ligand. Fusion of PEP1 to a model protein enabled receptor-mediated targeting to intestinal M-cell-associated regions and resulted in increased mucosal IgA and systemic IgG responses relative to the untargeted protein. Together, these findings establish PEP1 as a minimal peptide ligand that promotes receptor-mediated antigen uptake through M cells, demonstrating the utility of structure-guided approaches for discovering functional targeting peptides.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118579"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2026-02-02DOI: 10.1016/j.bmc.2026.118580
Shiv K. Sharma , Jacqueline R. Phan , Efren Heredia , Ernesto Abel-Santos , Steven M. Firestine
Clostridioides difficile is an anaerobic bacterium that is responsible for most antibiotic-associated cases of diarrhea. Clostridioides difficile infection (CDI) begins with the ingestion of an environmentally stable spore that germinates within the GI tract if the concentration and composition of bile salts, ions, and amino acids are favorable. We have shown that the bile salt analog N-phenyl-cholan-24-amide (1) can inhibit spore germination and prevent CDI in animal models of infection. Unfortunately, 1, while stable in the gut of antibiotic-treated animals, is rapidly degraded by normal gastrointestinal microbiota to release cholate and aniline. This instability prevents its use as a prophylactic for CDI. To generate more stable bile salt analogs, we removed the amide by either reducing it to an amine or converting it into 5,6-fused heterocycles. We found that reduction of the amide to an amine resulted in a significant loss of activity, but cyclization to benzimidazole (6a), benzothiazole (6b), or benzoxazole (6c) gave anti-germinants with good IC50 values. Changes in the sterane group to chenodeoxycholate and deoxycholate gave active compounds only for the benzimidazole series. Mice treated for 7 days with 6a and 6b showed no signs of toxicity up to 300 mg/kg/day. Compound 6b, but not 6a, was able to prevent CDI in a murine model of CDI when given at a dose of 50 mg/kg for three days. Examination of 6b showed that it was stable for 96 h in the presence of feces taken from healthy mice validating the hypothesis that replacing the amide with a bioisostere could increase the stability of the compound.
{"title":"5,6-Fused heterocycle cholate derivatives as spore germination inhibitors of Clostridioides difficile","authors":"Shiv K. Sharma , Jacqueline R. Phan , Efren Heredia , Ernesto Abel-Santos , Steven M. Firestine","doi":"10.1016/j.bmc.2026.118580","DOIUrl":"10.1016/j.bmc.2026.118580","url":null,"abstract":"<div><div><em>Clostridioides difficile</em> is an anaerobic bacterium that is responsible for most antibiotic-associated cases of diarrhea. <em>Clostridioides difficile</em> infection (CDI) begins with the ingestion of an environmentally stable spore that germinates within the GI tract if the concentration and composition of bile salts, ions, and amino acids are favorable. We have shown that the bile salt analog <em>N</em>-phenyl-cholan-24-amide (<strong>1</strong>) can inhibit spore germination and prevent CDI in animal models of infection. Unfortunately, <strong>1</strong>, while stable in the gut of antibiotic-treated animals, is rapidly degraded by normal gastrointestinal microbiota to release cholate and aniline. This instability prevents its use as a prophylactic for CDI. To generate more stable bile salt analogs, we removed the amide by either reducing it to an amine or converting it into 5,6-fused heterocycles. We found that reduction of the amide to an amine resulted in a significant loss of activity, but cyclization to benzimidazole (<strong>6a</strong>), benzothiazole (<strong>6b</strong>), or benzoxazole (<strong>6c</strong>) gave anti-germinants with good IC<sub>50</sub> values. Changes in the sterane group to chenodeoxycholate and deoxycholate gave active compounds only for the benzimidazole series. Mice treated for 7 days with <strong>6a</strong> and <strong>6b</strong> showed no signs of toxicity up to 300 mg/kg/day. Compound <strong>6b</strong>, but not <strong>6a</strong>, was able to prevent CDI in a murine model of CDI when given at a dose of 50 mg/kg for three days. Examination of <strong>6b</strong> showed that it was stable for 96 h in the presence of feces taken from healthy mice validating the hypothesis that replacing the amide with a bioisostere could increase the stability of the compound.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118580"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2026-01-19DOI: 10.1016/j.bmc.2026.118568
Chenliang Zhao , Yinxiao Du , Yixuan Xia , Baisen Chen , Zhongyi Seng , Kanglun Liu , Chushing Lam , Juan Zou , Hongjie Zhang
Ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F) is a naturally occurring ent-kaurane diterpenoid isolated from the traditional Chinese herbal medicine Pteris semipinnata L., a fern plant known for its reported antitumor properties. In an effort to expand the pool of natural scaffold-based compounds for anticancer purposes, novel derivatives of 5F have been synthesized by modifying functional groups at C-11 and C-19. These derivatives have been evaluated for their anti-proliferative activities against a panel of cancer cell lines. Among them, compound 13 exhibited approximately 27 times greater potency than 5F in HCT116 cells, with an IC50 value of 0.232 μM. In an HCT116 xenograft mouse model, 13 displayed superior tumor inhibitory effects compared to fluorouracil (5-FU).
{"title":"Design, synthesis and biological evaluation of new ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F) derivatives as potential antitumor agents","authors":"Chenliang Zhao , Yinxiao Du , Yixuan Xia , Baisen Chen , Zhongyi Seng , Kanglun Liu , Chushing Lam , Juan Zou , Hongjie Zhang","doi":"10.1016/j.bmc.2026.118568","DOIUrl":"10.1016/j.bmc.2026.118568","url":null,"abstract":"<div><div><em>Ent</em>-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F) is a naturally occurring <em>ent</em>-kaurane diterpenoid isolated from the traditional Chinese herbal medicine <em>Pteris semipinnata</em> L., a fern plant known for its reported antitumor properties. In an effort to expand the pool of natural scaffold-based compounds for anticancer purposes, novel derivatives of 5F have been synthesized by modifying functional groups at C-11 and C-19. These derivatives have been evaluated for their anti-proliferative activities against a panel of cancer cell lines. Among them, compound <strong>13</strong> exhibited approximately 27 times greater potency than 5F in HCT116 cells, with an IC<sub>50</sub> value of 0.232 μM. In an HCT116 xenograft mouse model, <strong>13</strong> displayed superior tumor inhibitory effects compared to fluorouracil (5-FU).</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118568"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2026-01-17DOI: 10.1016/j.bmc.2026.118573
Uriel Matthew Enriquez , Natalie M. González Velázquez , Mohammad Mosharraf Hossain , Jillian L. Kyzer , Ilia A. Guzei , Cody J. Wenthur
Antibodies against small psychoactive molecules have been developed for applications ranging from substance detection and overdose protection to mechanistic understanding of the actions of complex substance mixtures. In this study, we describe the design, synthesis, formulation, and animal testing of an initial immunogenic bioconjugate, as well as subsequent isolation of enantiospecific monoclonal antibodies against (2R,6R)-hydroxynorketamine, a putatively active metabolite of the dissociative-anesthetic and rapidly-acting antidepressant ketamine. Following pharmacophore synthesis, hapten generation was achieved through installation of 6-aminohexanoic acid linkers using reductive amination. Bioconjugation to the carrier protein, cross-reactive material 197 (CRM) was achieved via amide coupling. Upon administration to mice in combination with alum and CpG oligodeoxynucleotide 1826, (2R,6R)-hydroxynorketamine-CRM generated equivalent antibody titers to a comparator racemic 6-hydroxynorketamine-CRM hapten. Following creation of hybridomas arising from B-cells responsive to (2R,6R)-hydroxynorketamine-CRM exposure and subsequent screening, subcloning, sequencing, and production, we were able to identify a monoclonal antibody, 6F11-HC1-LC2, which yielded antibodies strongly responsive to (2R,6R)-hydroxynorketamine, but showed no responsiveness to (2S,6S)-hydroxynorketamine in a competitive binding enzyme-linked immunosorbent assay format. Surface plasmon resonance analysis of this monoclonal species demonstrated sub-nanomolar (0.4 nM) antibody affinity for (2R,6R)-hydroxynorketamine-BSA bioconjugates and > 150-fold selectivity in comparison to ketamine-BSA bioconjugates. Overall, these results demonstrate successful production of monoclonal antibodies capable of robustly distinguishing between hydroxynorketamine enantiomers, enabling their use in future in vivo studies to better understand their relative contributions to the rapidly-acting antidepressant properties of ketamine.
{"title":"Generation of enantiospecific monoclonal antibodies against (2R,6R)-hydroxynorketamine","authors":"Uriel Matthew Enriquez , Natalie M. González Velázquez , Mohammad Mosharraf Hossain , Jillian L. Kyzer , Ilia A. Guzei , Cody J. Wenthur","doi":"10.1016/j.bmc.2026.118573","DOIUrl":"10.1016/j.bmc.2026.118573","url":null,"abstract":"<div><div>Antibodies against small psychoactive molecules have been developed for applications ranging from substance detection and overdose protection to mechanistic understanding of the actions of complex substance mixtures. In this study, we describe the design, synthesis, formulation, and animal testing of an initial immunogenic bioconjugate, as well as subsequent isolation of enantiospecific monoclonal antibodies against (<em>2R,6R</em>)-hydroxynorketamine, a putatively active metabolite of the dissociative-anesthetic and rapidly-acting antidepressant ketamine. Following pharmacophore synthesis, hapten generation was achieved through installation of 6-aminohexanoic acid linkers using reductive amination. Bioconjugation to the carrier protein, cross-reactive material 197 (CRM) was achieved via amide coupling. Upon administration to mice in combination with alum and CpG oligodeoxynucleotide 1826, (<em>2R,6R</em>)-hydroxynorketamine-CRM generated equivalent antibody titers to a comparator racemic 6-hydroxynorketamine-CRM hapten. Following creation of hybridomas arising from B-cells responsive to (<em>2R,6R</em>)-hydroxynorketamine-CRM exposure and subsequent screening, subcloning, sequencing, and production, we were able to identify a monoclonal antibody, 6F11-HC<sub>1</sub>-LC<sub>2</sub>, which yielded antibodies strongly responsive to (<em>2R,6R</em>)-hydroxynorketamine, but showed no responsiveness to (<em>2S,6S</em>)-hydroxynorketamine in a competitive binding enzyme-linked immunosorbent assay format. Surface plasmon resonance analysis of this monoclonal species demonstrated sub-nanomolar (0.4 nM) antibody affinity for (<em>2R,6R</em>)-hydroxynorketamine-BSA bioconjugates and > 150-fold selectivity in comparison to ketamine-BSA bioconjugates. Overall, these results demonstrate successful production of monoclonal antibodies capable of robustly distinguishing between hydroxynorketamine enantiomers, enabling their use in future in vivo studies to better understand their relative contributions to the rapidly-acting antidepressant properties of ketamine.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118573"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The identification of novel candidate molecules with breakthrough potential is critical for advancing breast cancer therapy. Lasioglossum-III (LL-III), a linear peptide isolated from wild bee venom, has emerged as a promising lead compound for breast cancer treatment. However, its therapeutic potential is limited by poor membrane permeability and low stability, which are common limitations of linear peptides. To overcome these challenges, we applied an all-hydrocarbon stapling strategy to design and synthesize a series of LL-III stapled peptides and systematically evaluated their physicochemical properties and antitumor activities. Among the derivatives, LL-III-4 exhibited the most pronounced overall improvements, including enhanced α-helicity, increased protease resistance, improved membrane permeability, strengthened apoptosis induction, elevated in intro antitumor efficacy, and augmented inhibition of tubulin polymerization. Collectively, this study demonstrates that all-hydrocarbon stapling effectively optimizes the secondary structure, stability, and biological activity of LL-III, providing a novel drug candidate for breast cancer therapy.
发现具有突破性潜力的新型候选分子对推进乳腺癌治疗至关重要。lasioglossumi - iii （LL-III）是一种从野生蜂毒中分离出来的线状肽，已成为治疗乳腺癌的有前途的先导化合物。然而，它的治疗潜力受到膜渗透性差和稳定性低的限制，这是线性肽的共同局限性。为了克服这些挑战，我们采用全碳氢化合物钉接策略设计并合成了一系列LL-III钉接肽，并系统地评估了它们的理化性质和抗肿瘤活性。在这些衍生物中，LL-III-4表现出最明显的整体改善，包括α-螺旋度增强、蛋白酶抗性增强、膜通透性改善、细胞凋亡诱导增强、抗肿瘤作用增强、微管蛋白聚合抑制增强。综上所述，本研究表明，全烃吻合器有效地优化了LL-III的二级结构、稳定性和生物活性，为乳腺癌治疗提供了一种新的候选药物。
{"title":"Hydrocarbon stapling strategy and antitumor activity of antimicrobial peptide Lasioglossum III.","authors":"Jinqiu Li, Jiayi Zhu, Xinhao Wei, Yaojin Zhu, Jingfei Xu, Fei Gao, Honggang Hu, Shipeng He","doi":"10.1016/j.bmc.2026.118639","DOIUrl":"https://doi.org/10.1016/j.bmc.2026.118639","url":null,"abstract":"<p><p>The identification of novel candidate molecules with breakthrough potential is critical for advancing breast cancer therapy. Lasioglossum-III (LL-III), a linear peptide isolated from wild bee venom, has emerged as a promising lead compound for breast cancer treatment. However, its therapeutic potential is limited by poor membrane permeability and low stability, which are common limitations of linear peptides. To overcome these challenges, we applied an all-hydrocarbon stapling strategy to design and synthesize a series of LL-III stapled peptides and systematically evaluated their physicochemical properties and antitumor activities. Among the derivatives, LL-III-4 exhibited the most pronounced overall improvements, including enhanced α-helicity, increased protease resistance, improved membrane permeability, strengthened apoptosis induction, elevated in intro antitumor efficacy, and augmented inhibition of tubulin polymerization. Collectively, this study demonstrates that all-hydrocarbon stapling effectively optimizes the secondary structure, stability, and biological activity of LL-III, providing a novel drug candidate for breast cancer therapy.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"137 ","pages":"118639"},"PeriodicalIF":3.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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