Pub Date : 2024-12-10DOI: 10.1021/acs.jmedchem.4c01725
Jeffrey W. Johannes, Amber Y. S. Balazs, Derek Barratt, Michal Bista, Matthew D. Chuba, Sabina Cosulich, Susan E. Critchlow, Sébastien L. Degorce, Paolo Di Fruscia, Scott D. Edmondson, Kevin J. Embrey, Stephen Fawell, Avipsa Ghosh, Sonja J. Gill, Anders Gunnarsson, Sudhir M. Hande, Tom D. Heightman, Paul Hemsley, Giuditta Illuzzi, Jordan Lane, Carrie J.B. Larner, Elisabetta Leo, Lina Liu, Andrew Madin, Lisa McWilliams, Mark J. O’Connor, Jonathan P. Orme, Fiona Pachl, Martin J. Packer, Xiaohui Pei, Andy Pike, Marianne Schimpl, Hongyao She, Anna D. Staniszewska, Verity Talbot, Elizabeth Underwood, Jeffrey G. Varnes, Lin Xue, Tieguang Yao, Ke Zhang, Andrew X. Zhang, Xiaolan Zheng
PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper. AZD5305 maintained the antitumor efficacy of first-generation PARP inhibitors while exhibiting lower hematological toxicity. Recently, there has been interest in central nervous system (CNS)-penetrant PARP inhibitors for CNS malignancies and other neurological conditions; however, AZD5305 is not CNS penetrant. Herein we describe the discovery and optimization of a series of CNS-penetrant, PARP1-selective inhibitors and PARP1-DNA trappers, culminating in the discovery of AZD9574, a compound that maintains the PARP1 selectivity of AZD5305 with improved permeability, reduced efflux, and increased CNS penetration.
{"title":"Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor","authors":"Jeffrey W. Johannes, Amber Y. S. Balazs, Derek Barratt, Michal Bista, Matthew D. Chuba, Sabina Cosulich, Susan E. Critchlow, Sébastien L. Degorce, Paolo Di Fruscia, Scott D. Edmondson, Kevin J. Embrey, Stephen Fawell, Avipsa Ghosh, Sonja J. Gill, Anders Gunnarsson, Sudhir M. Hande, Tom D. Heightman, Paul Hemsley, Giuditta Illuzzi, Jordan Lane, Carrie J.B. Larner, Elisabetta Leo, Lina Liu, Andrew Madin, Lisa McWilliams, Mark J. O’Connor, Jonathan P. Orme, Fiona Pachl, Martin J. Packer, Xiaohui Pei, Andy Pike, Marianne Schimpl, Hongyao She, Anna D. Staniszewska, Verity Talbot, Elizabeth Underwood, Jeffrey G. Varnes, Lin Xue, Tieguang Yao, Ke Zhang, Andrew X. Zhang, Xiaolan Zheng","doi":"10.1021/acs.jmedchem.4c01725","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01725","url":null,"abstract":"PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper. AZD5305 maintained the antitumor efficacy of first-generation PARP inhibitors while exhibiting lower hematological toxicity. Recently, there has been interest in central nervous system (CNS)-penetrant PARP inhibitors for CNS malignancies and other neurological conditions; however, AZD5305 is not CNS penetrant. Herein we describe the discovery and optimization of a series of CNS-penetrant, PARP1-selective inhibitors and PARP1-DNA trappers, culminating in the discovery of AZD9574, a compound that maintains the PARP1 selectivity of AZD5305 with improved permeability, reduced efflux, and increased CNS penetration.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"237 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797681","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}
Development of different platforms would be useful for designing functional antibodies to improve the efficiency of antibody-based drugs. Three-dimensional domain swapping (3D-DS) may occur in the variable region of antibody light chain #4C214A, and a pair of domain-swapped dimers may interact with each other to form a tetramer. In this study, to stabilize the 3D-DS dimer structure in #4C214A, Val2 in strand A (swapping region) and Thr97 in strand G were replaced with Cys residues, generating #4 V2C/T97C/C214A with a Cys2–Cys97 disulfide bond that cross-links strands A and G of different protomers. The #4 V2C/T97C/C214A tetramer did not dissociate into monomers at low protein concentration (6 μM); however, some of the tetramers were converted to monomers by disulfide bond reduction. Two-dimensional free energy profile analysis for the tetramerization of two 3D-DS dimers was performed by molecular dynamics simulation. These results show that disulfide bond introduction is useful for controlling the dimerization/dissociation of the variable region through 3D-DS.
{"title":"Experimental and Computational Studies on Domain-Swapped Structure Stabilization of an Antibody Light Chain by Disulfide Bond Introduction","authors":"Wahyu Fitriana, Takahiro Sakai, Lian Duan, Kowit Hengphasatporn, Yasuteru Shigeta, Tsuyoshi Mashima, Taizo Uda, Emi Hifumi, Shun Hirota","doi":"10.1021/acs.jmedchem.4c02570","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02570","url":null,"abstract":"Development of different platforms would be useful for designing functional antibodies to improve the efficiency of antibody-based drugs. Three-dimensional domain swapping (3D-DS) may occur in the variable region of antibody light chain #4C214A, and a pair of domain-swapped dimers may interact with each other to form a tetramer. In this study, to stabilize the 3D-DS dimer structure in #4C214A, Val2 in strand A (swapping region) and Thr97 in strand G were replaced with Cys residues, generating #4 V2C/T97C/C214A with a Cys2–Cys97 disulfide bond that cross-links strands A and G of different protomers. The #4 V2C/T97C/C214A tetramer did not dissociate into monomers at low protein concentration (6 μM); however, some of the tetramers were converted to monomers by disulfide bond reduction. Two-dimensional free energy profile analysis for the tetramerization of two 3D-DS dimers was performed by molecular dynamics simulation. These results show that disulfide bond introduction is useful for controlling the dimerization/dissociation of the variable region through 3D-DS.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"28 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797733","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 : 2024-12-10DOI: 10.1021/acs.jmedchem.4c02286
Anne Marie Prentiss, Carlo Baggio, James Pagett, Anna O. Kulinich, Iryna M. Ethell, Kendall Muzzarelli, Zahra Assar, Maurizio Pellecchia
The activity of the receptor tyrosine kinase EphA4 has been implicated in several pathologies including oncology (gastric and pancreatic cancers) and neurodegenerative diseases (amyotrophic lateral sclerosis and Alzheimer’s disease). However, advances in validating EphA4 as a possible drug target have been limited by the lack of suitable pharmacological inhibitors. Recently, we reported on the design of potent EphA4 agonistic agents targeting its ligand binding domain (LBD). Based on previous studies with a phage display cyclic peptide inhibitor, we designed a β-hairpin mimetic with high affinity for EphA4-LBD. These agents hold great promise for further validation and development of EphA4-based therapeutics. Moreover, our studies introduce a possible strategy for the design of constrained β-hairpin peptides.
{"title":"Constrained β-Hairpins Targeting the EphA4 Ligand Binding Domain","authors":"Anne Marie Prentiss, Carlo Baggio, James Pagett, Anna O. Kulinich, Iryna M. Ethell, Kendall Muzzarelli, Zahra Assar, Maurizio Pellecchia","doi":"10.1021/acs.jmedchem.4c02286","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02286","url":null,"abstract":"The activity of the receptor tyrosine kinase EphA4 has been implicated in several pathologies including oncology (gastric and pancreatic cancers) and neurodegenerative diseases (amyotrophic lateral sclerosis and Alzheimer’s disease). However, advances in validating EphA4 as a possible drug target have been limited by the lack of suitable pharmacological inhibitors. Recently, we reported on the design of potent EphA4 agonistic agents targeting its ligand binding domain (LBD). Based on previous studies with a phage display cyclic peptide inhibitor, we designed a β-hairpin mimetic with high affinity for EphA4-LBD. These agents hold great promise for further validation and development of EphA4-based therapeutics. Moreover, our studies introduce a possible strategy for the design of constrained β-hairpin peptides.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"97 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797682","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 : 2024-12-10DOI: 10.1021/acs.jmedchem.4c01354
Xiaoxuan Yu, Yanyu Zhou, Xiaoyan Ma, Wan Zhang, Fuwei Li, Fengyu Jiang, Yawen Wang, Qin Zhang, Wukun Liu
Inducing differentiation of leukemia cells into dendritic cells (DC) is pivotal to reshaping the immunosuppressive microenvironment. Here, we report the synthesis of EG2, an erlotinib-gold(I) complex, which directly prompts the differentiation of acute myeloid leukemia (AML) cells into DCs. A patient-derived xenograft (PDX) model underscores the potent anti-AML activity of EG2. Mechanistic studies reveal that EG2 initiates the activation of the PPARγ/RXRα heterodimer by targeting thioredoxin reductase (TrxR) and the epidermal growth factor receptor (EGFR). This activation culminates in the expression of genes associated with the differentiation of the AML cells into DCs as well as pyroptosis, effectively reshaping the immune microenvironment both in vitro and in vivo. Overall, this study marks the first instance of a gold-based small molecule inducing the direct differentiation of tumor cells into immune cells and offers a promising and innovative strategy for the design of AML immunotherapies.
{"title":"Erlotinib-Gold(I) Complex Induces Leukemia Cell DC Differentiation and Remodels the Immunosuppressive Microenvironment","authors":"Xiaoxuan Yu, Yanyu Zhou, Xiaoyan Ma, Wan Zhang, Fuwei Li, Fengyu Jiang, Yawen Wang, Qin Zhang, Wukun Liu","doi":"10.1021/acs.jmedchem.4c01354","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01354","url":null,"abstract":"Inducing differentiation of leukemia cells into dendritic cells (DC) is pivotal to reshaping the immunosuppressive microenvironment. Here, we report the synthesis of <b>EG2</b>, an erlotinib-gold(I) complex, which directly prompts the differentiation of acute myeloid leukemia (AML) cells into DCs. A patient-derived xenograft (PDX) model underscores the potent anti-AML activity of <b>EG2</b>. Mechanistic studies reveal that <b>EG2</b> initiates the activation of the PPARγ/RXRα heterodimer by targeting thioredoxin reductase (TrxR) and the epidermal growth factor receptor (EGFR). This activation culminates in the expression of genes associated with the differentiation of the AML cells into DCs as well as pyroptosis, effectively reshaping the immune microenvironment both <i>in vitro and in vivo</i>. Overall, this study marks the first instance of a gold-based small molecule inducing the direct differentiation of tumor cells into immune cells and offers a promising and innovative strategy for the design of AML immunotherapies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797680","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}
The genetic recombination and antigenic variation of influenza viruses may decrease the efficacy of antiviral vaccines, highlighting the imperativeness of developing novel anti-influenza agents. Herein, a series of thiophene-based compounds were designed and synthesized as potent anti-influenza agents. Among them, ATV2301 exhibited an excellent anti-influenza activity (EC50, H1N1 = 1.88 nM, H3N2 = 4.77 nM), a higher safety index (SI, H1N1 = 18218, H3N2 = 7180), and a remarkably improved oral bioavailability (F = 71.60%). The prodrug ATV2301A demonstrated strong therapeutic efficacy and protection in H1N1-infected BALB/c mice, with low toxicity and broad tissue distribution. ATV2301 also exhibited high stability in both human and mouse liver microsomes. Mechanistic studies indicated that ATV2301’s anti-influenza activity was due to its effects on polymerase acid protein (PA), nuclear protein (NP), and RNA-dependent RNA polymerase (RdRp). Additionally, ATV2301 showed potent activities against clinical isolates of anti-influenza A virus (IAV) and anti-influenza B virus (IBV), positioning it as a promising cap-dependent endonuclease inhibitor for further clinical research.
{"title":"Discovery of Novel Thiophene-Based Baloxavir Derivatives as Potent Cap-Dependent Endonuclease Inhibitors for Influenza Treatment","authors":"Yongzhi Chen, Kunyu Lu, Binhao Rong, Yuanmei Wen, Guanguan Li, Shuo Li, Deyin Guo, Qifan Zhou, Shuwen Liu, Xumu Zhang","doi":"10.1021/acs.jmedchem.4c01979","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01979","url":null,"abstract":"The genetic recombination and antigenic variation of influenza viruses may decrease the efficacy of antiviral vaccines, highlighting the imperativeness of developing novel anti-influenza agents. Herein, a series of thiophene-based compounds were designed and synthesized as potent anti-influenza agents. Among them, <b>ATV2301</b> exhibited an excellent anti-influenza activity (EC<sub>50</sub>, H1N1 = 1.88 nM, H3N2 = 4.77 nM), a higher safety index (SI, H1N1 = 18218, H3N2 = 7180), and a remarkably improved oral bioavailability (<i>F</i> = 71.60%). The prodrug <b>ATV2301A</b> demonstrated strong therapeutic efficacy and protection in H1N1-infected BALB/c mice, with low toxicity and broad tissue distribution. <b>ATV2301</b> also exhibited high stability in both human and mouse liver microsomes. Mechanistic studies indicated that <b>ATV2301</b>’s anti-influenza activity was due to its effects on polymerase acid protein (PA), nuclear protein (NP), and RNA-dependent RNA polymerase (RdRp). Additionally, <b>ATV2301</b> showed potent activities against clinical isolates of anti-influenza A virus (IAV) and anti-influenza B virus (IBV), positioning it as a promising cap-dependent endonuclease inhibitor for further clinical research.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"24 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805054","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 : 2024-12-09DOI: 10.1021/acs.jmedchem.4c02876
Tomayo Berida, Craig W. Lindsley
Figure 1. Antitubercular drugs in clinical use. (3,4) Table one was adapted from WHO’s 2023 Antibacterial agents in clinical and preclinical development. (16) NCR: No cross resistance, NCC: New chemical class; NT: New target; MoA: New mechanism of Action. Figure 2. Antitubercular agent in clinical development. Figure 3. Cell wall of mycobacteria (left), Gram-positive bacteria (center), and Gram-negative bacteria (right). The figure was adapted from “Plant Antibacterials: The Challenges and Opportunities”, Berida et al, Heliyon2024, 10 (10), e31145, with permission from Elsevier. (26) This article references 38 other publications. This article has not yet been cited by other publications.
{"title":"Move over COVID, Tuberculosis Is Once again the Leading Cause of Death from a Single Infectious Disease","authors":"Tomayo Berida, Craig W. Lindsley","doi":"10.1021/acs.jmedchem.4c02876","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02876","url":null,"abstract":"Figure 1. Antitubercular drugs in clinical use. (3,4) Table one was adapted from WHO’s 2023 Antibacterial agents in clinical and preclinical development. (16) NCR: No cross resistance, NCC: New chemical class; NT: New target; MoA: New mechanism of Action. Figure 2. Antitubercular agent in clinical development. Figure 3. Cell wall of mycobacteria (left), Gram-positive bacteria (center), and Gram-negative bacteria (right). The figure was adapted from “Plant Antibacterials: The Challenges and Opportunities”, Berida et al, <i>Heliyon</i> <b>2024</b>, 10 (10), e31145, with permission from Elsevier. (26) This article references 38 other publications. This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797734","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 : 2024-12-09DOI: 10.1021/acs.jmedchem.4c01801
Ke Li, Xing Hu, Xin-Yi Tu, Mao-Ying Xian, Lei-Lei Huang, Ting Huang, Rui Luo, Hui Jin, Zheng Liu
The controlled release of immunostimulatory agents represents a promising strategy to enhance vaccine efficacy while minimizing side effects. This study aimed to improve the efficacy of the RBD-Fc-based COVID-19 vaccine through combining of an iNKT cell agonist and a TLR7/8 agonist using covalent conjugation and temporal delivery. We hypothesized that these combinations would yield a more balanced Th1/Th2 immune response. For covalent conjugation, we employed an uncleavable linker and a self-immolative disulfide linker to conjugate α-galactosylceramide (αGC) to imidazoquinoline (IMDQ). The αGC-SS-IMDQ-Ac conjugate, designed with a prodrug strategy for controlled TLR7/8 agonist release, elicited a higher IFN-γ/IL-4 T cell response ratio than individual adjuvants or their admixture. In the temporal delivery approach, administering IMDQ followed by αGC after 2 h resulted in the highest IgG2a/IgG1 ratio, significantly surpassing other groups. A 6 h delay between glycolipid and IMDQ injections yielded balanced IgG responses, enhancing IgG, IgG1, and IgG2a levels synergistically.
{"title":"Enhancing COVID-19 Vaccine Efficacy: Dual Adjuvant Strategies with TLR7/8 Agonists and Glycolipids","authors":"Ke Li, Xing Hu, Xin-Yi Tu, Mao-Ying Xian, Lei-Lei Huang, Ting Huang, Rui Luo, Hui Jin, Zheng Liu","doi":"10.1021/acs.jmedchem.4c01801","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01801","url":null,"abstract":"The controlled release of immunostimulatory agents represents a promising strategy to enhance vaccine efficacy while minimizing side effects. This study aimed to improve the efficacy of the RBD-Fc-based COVID-19 vaccine through combining of an iNKT cell agonist and a TLR7/8 agonist using covalent conjugation and temporal delivery. We hypothesized that these combinations would yield a more balanced Th1/Th2 immune response. For covalent conjugation, we employed an uncleavable linker and a self-immolative disulfide linker to conjugate α-galactosylceramide (αGC) to imidazoquinoline (IMDQ). The αGC-SS-IMDQ-Ac conjugate, designed with a prodrug strategy for controlled TLR7/8 agonist release, elicited a higher IFN-γ/IL-4 T cell response ratio than individual adjuvants or their admixture. In the temporal delivery approach, administering IMDQ followed by αGC after 2 h resulted in the highest IgG2a/IgG1 ratio, significantly surpassing other groups. A 6 h delay between glycolipid and IMDQ injections yielded balanced IgG responses, enhancing IgG, IgG1, and IgG2a levels synergistically.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"200 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793804","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 : 2024-12-09DOI: 10.1021/acs.jmedchem.4c02624
Qiuyue Zhang, Jia Yu, Qidong You, Lei Wang
Abnormal phosphorylation of proteins can lead to various diseases, particularly cancer. Therefore, the development of small molecules for precise regulation of protein phosphorylation holds great potential for drug design. While the traditional kinase/phosphatase small-molecule modulators have shown some success, achieving precise phosphorylation regulation has proven to be challenging. The emergence of heterobifunctional molecules, such as phosphorylation-inducing chimeric small molecules (PHICSs) and phosphatase recruiting chimeras (PHORCs), with proximity-inducing modalities is expected to lead to a breakthrough by specifically recruiting kinase or phosphatase to the protein of interest. Herein, we summarize the drug targets with aberrant phosphorylation in cancer and underscore the potential of correcting phosphorylation in cancer therapy. Through reported cases of heterobifunctional molecules targeting phosphorylation regulation, we highlight the current design strategies and features of these molecules. We also provide a systematic elaboration of the link between aberrantly phosphorylated targets and cancer as well as the existing challenges and future research directions for developing heterobifunctional molecular drugs for phosphorylation regulation.
{"title":"Modulating Phosphorylation by Proximity-Inducing Modalities for Cancer Therapy","authors":"Qiuyue Zhang, Jia Yu, Qidong You, Lei Wang","doi":"10.1021/acs.jmedchem.4c02624","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02624","url":null,"abstract":"Abnormal phosphorylation of proteins can lead to various diseases, particularly cancer. Therefore, the development of small molecules for precise regulation of protein phosphorylation holds great potential for drug design. While the traditional kinase/phosphatase small-molecule modulators have shown some success, achieving precise phosphorylation regulation has proven to be challenging. The emergence of heterobifunctional molecules, such as phosphorylation-inducing chimeric small molecules (PHICSs) and phosphatase recruiting chimeras (PHORCs), with proximity-inducing modalities is expected to lead to a breakthrough by specifically recruiting kinase or phosphatase to the protein of interest. Herein, we summarize the drug targets with aberrant phosphorylation in cancer and underscore the potential of correcting phosphorylation in cancer therapy. Through reported cases of heterobifunctional molecules targeting phosphorylation regulation, we highlight the current design strategies and features of these molecules. We also provide a systematic elaboration of the link between aberrantly phosphorylated targets and cancer as well as the existing challenges and future research directions for developing heterobifunctional molecular drugs for phosphorylation regulation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"83 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793722","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 : 2024-12-09DOI: 10.1021/acs.jmedchem.4c01930
Rebecca A. Gallego, Sujin Cho-Schultz, Matthew Del Bel, Anne-Marie Dechert-Schmitt, Joyann S. Donaldson, Mingying He, Mehran Jalaie, Rob Kania, Jean Matthews, Michele McTigue, Jamison B. Tuttle, Hud Risley, Dahui Zhou, Ru Zhou, Omar K. Ahmad, Louise Bernier, Simon Berritt, John Braganza, Zecheng Chen, Julie A. Cianfrogna, Michael Collins, Cinthia Costa Jones, Ciaran N. Cronin, Carl Davis, Klaus Dress, Martin Edwards, William Farrell, Scott P. France, Nicole Grable, Eric Johnson, Ted W. Johnson, Rhys Jones, Thomas Knauber, Jennifer Lafontaine, Richard P. Loach, Michael Maestre, Nichol Miller, Mark Moen, Sebastien Monfette, Peter Morse, Andrew Ross Nager, Mark Niosi, Paul Richardson, Allison K. Rohner, Neal W. Sach, Sergei Timofeevski, Joseph W. Tucker, Beth Vetelino, Lei Zhang, Sajiv K. Nair
Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents a high interest target for the treatment of cancer through an immune-mediated mechanism. Herein we present highlights of the drug discovery campaign within the lactam/azalactam series of inhibitors that yielded a small molecule (21, PF-07265028), which was advanced to a phase 1 clinical trial (NCT05233436). Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1. Structure-based drug design via leveraging cocrystal structures and lipophilic efficiency analysis proved to be valuable tools that ultimately enabled the delivery of a clinical-quality small molecule inhibitor of HPK1.
{"title":"Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer","authors":"Rebecca A. Gallego, Sujin Cho-Schultz, Matthew Del Bel, Anne-Marie Dechert-Schmitt, Joyann S. Donaldson, Mingying He, Mehran Jalaie, Rob Kania, Jean Matthews, Michele McTigue, Jamison B. Tuttle, Hud Risley, Dahui Zhou, Ru Zhou, Omar K. Ahmad, Louise Bernier, Simon Berritt, John Braganza, Zecheng Chen, Julie A. Cianfrogna, Michael Collins, Cinthia Costa Jones, Ciaran N. Cronin, Carl Davis, Klaus Dress, Martin Edwards, William Farrell, Scott P. France, Nicole Grable, Eric Johnson, Ted W. Johnson, Rhys Jones, Thomas Knauber, Jennifer Lafontaine, Richard P. Loach, Michael Maestre, Nichol Miller, Mark Moen, Sebastien Monfette, Peter Morse, Andrew Ross Nager, Mark Niosi, Paul Richardson, Allison K. Rohner, Neal W. Sach, Sergei Timofeevski, Joseph W. Tucker, Beth Vetelino, Lei Zhang, Sajiv K. Nair","doi":"10.1021/acs.jmedchem.4c01930","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01930","url":null,"abstract":"Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents a high interest target for the treatment of cancer through an immune-mediated mechanism. Herein we present highlights of the drug discovery campaign within the lactam/azalactam series of inhibitors that yielded a small molecule (<b>21</b>, PF-07265028), which was advanced to a phase 1 clinical trial (NCT05233436). Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1. Structure-based drug design via leveraging cocrystal structures and lipophilic efficiency analysis proved to be valuable tools that ultimately enabled the delivery of a clinical-quality small molecule inhibitor of HPK1.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"211 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793805","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}
High mobility group box 1 (HMGB1) is a nonhistone chromatin protein predominantly located in the nucleus. However, under pathological conditions, HMGB1 can translocate from the nucleus to the cytoplasm and subsequently be released into the extracellular space through both active secretion and passive release mechanisms. The distinct cellular locations of HMGB1 facilitate its interaction with various endogenous and exogenous factors, allowing it to perform diverse functions across a range of diseases. This Perspective provides a comprehensive overview of the structure, release mechanisms, and multifaceted roles of HMGB1 in disease contexts. Furthermore, it introduces the development of both small molecule and macromolecule inhibitors targeting HMGB1 and its interaction with receptors. A detailed analysis of the predicted pockets is also presented, aiming to establish a foundation for the future design and development of HMGB1 inhibitors.
{"title":"Targeting HMGB1 and Its Interaction with Receptors: Challenges and Future Directions","authors":"Pingping Shen, Libang Zhang, Xuewa Jiang, Boyang Yu, Jian Zhang","doi":"10.1021/acs.jmedchem.4c01912","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01912","url":null,"abstract":"High mobility group box 1 (HMGB1) is a nonhistone chromatin protein predominantly located in the nucleus. However, under pathological conditions, HMGB1 can translocate from the nucleus to the cytoplasm and subsequently be released into the extracellular space through both active secretion and passive release mechanisms. The distinct cellular locations of HMGB1 facilitate its interaction with various endogenous and exogenous factors, allowing it to perform diverse functions across a range of diseases. This Perspective provides a comprehensive overview of the structure, release mechanisms, and multifaceted roles of HMGB1 in disease contexts. Furthermore, it introduces the development of both small molecule and macromolecule inhibitors targeting HMGB1 and its interaction with receptors. A detailed analysis of the predicted pockets is also presented, aiming to establish a foundation for the future design and development of HMGB1 inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793808","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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