Journal of Medicinal Chemistry最新文献

{"title":"Synergistic Cancer Therapy: An NIR-Activated Methylene Blue-Nitrogen Mustard Prodrug for Combined Chemotherapy and Photodynamic Therapy","authors":"Tianyu Zhu, Jipeng Ding, Fan Zheng, Yanpeng Fang, Wenzhi Huang, Ying Yin, Wenbin Zeng","doi":"10.1021/acs.jmedchem.5c00120","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00120","url":null,"abstract":"Nitrogen mustard, a widely used chemotherapeutic agent for more than 70 years, exhibits significant efficacy. However, its clinical applications are severely limited by poor tumor selectivity and severe side effects on normal tissues. To address these limitations, we developed a near-infrared (NIR)-activatable nitrogen mustard prodrug, <b>MBNM</b>. Upon NIR irradiation, the controlled cleavage of the urea bond within <b>MBNM</b> facilitates the simultaneous release of nitrogen mustard and methylene blue (MB), enabling a synergistic approach combining chemotherapy and photodynamic therapy (PDT) for effective tumor suppression. Moreover, the release of MB upon activation enables real-time monitoring of prodrug activation. Notably, <b>MBNM</b> demonstrated significantly improved biosafety compared to free nitrogen mustard. These findings suggest that the photocleavable prodrug <b>MBNM</b> offers a promising strategy for safe and effective combination cancer therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"15 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666677","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}

{"title":"Design and Development of a Novel BET Protein-Targeted PET Imaging Probe for In Vivo Characterization of Alzheimer’s Disease Pathophysiology","authors":"Yanli Wang, Yongle Wang, Yulong Xu, Hua Cheng, Tewodros Mulugeta Dagnew, Leyi Kang, Darcy Tocci, Iris Z. Shen, Can Zhang, Changning Wang","doi":"10.1021/acs.jmedchem.5c00068","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00068","url":null,"abstract":"BET proteins are essential epigenetic regulators involved in gene transcription and have been linked to neurodegenerative disorders, such as Alzheimer’s disease (AD). In vivo imaging of BET proteins may provide insights into disease pathophysiology and help identify potential therapeutic targets. We developed a carbon-¹¹-labeled radiotracer, [¹¹C]YL9, which exhibits high binding affinity for BET proteins. It was synthesized via standard methylation and evaluated for brain uptake, binding specificity, and pharmacokinetics in wild-type and AD mouse models using PET imaging and autoradiography. [¹¹C]YL9 demonstrated excellent blood-brain barrier penetration, prolonged retention, and strong BET protein binding. In AD mice, [¹¹C]YL9 uptake was significantly higher than in wild-type mice, suggesting increased BET protein availability. These findings suggest that [¹¹C]YL9 is a promising PET radioligand for noninvasive BET protein imaging. Its high specificity and favorable pharmacokinetics make it a valuable tool for studying BET protein involvement in neurodegeneration.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"56 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672787","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}

{"title":"Free Drug Concepts: A Lingering Problem in Drug Discovery","authors":"Peter J. H. Webborn, Kevin Beaumont, Iain J. Martin, Dennis A. Smith","doi":"10.1021/acs.jmedchem.5c00725","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00725","url":null,"abstract":"The concepts, while not complex, can be counterintuitive. The processes governing free drug concentrations &lt;i&gt;in vivo&lt;/i&gt; are different from those in &lt;i&gt;in vitro&lt;/i&gt; assays but are often assumed to be the same. The most common calculation performed (conversion of total drug concentration to free drug concentration) requires an equation in a form that, while mathematically correct, has led to a mechanistic misunderstanding. This misunderstanding results in many published studies being incorrect in their use of pharmacokinetic data as drivers of compound optimization. Pharmacokinetic training focuses on total drug concentrations and parameters, and these also dominate clinical pharmacokinetics where the focus is on a single compound, and for which plasma binding is usually constant. Compound optimization in drug discovery is anchored on the understanding of unbound drug exposure and its relationship to target engagement; thus, comparisons between molecules requires the use of unbound exposure and unbound PK parameters. Even today, authors use the term “Free drug hypothesis”, as though there is some doubt as to its validity. It is not a hypothesis; it is a fundamental principle. Unbound drug concentrations at the target site determine the degree of target engagement Unbound concentrations &lt;i&gt;in vivo&lt;/i&gt; are not determined by the extent of plasma or tissue binding; instead, plasma and tissue binding determine the concentrations of bound drug Unbound drug concentrations &lt;i&gt;in vivo&lt;/i&gt; are determined by the rate of drug input (absorption) and the rate of elimination (intrinsic clearance) At equilibrium, free drug concentrations in cytosol approximate those in plasma (with a few specific exceptions, described below Figure 1. Clearance terms derived from in vitro and in vivo experiments and their relationships Note: CLint is, by definition, an unbound term and thus CLint measured &lt;i&gt;in vitro&lt;/i&gt; is an apparent value until corrected for binding in the assay. However, for the avoidance of doubt, we have used CLint,u to represent the binding-corrected &lt;i&gt;in vitro&lt;/i&gt; value. Figure 2. Effect of increasing dose on the total and free AUC and clearance for ceftriaxone. Figure 3. Simulations demonstrating influence of plasma protein binding on pharmacokinetic parameters. Figure 4. Mean Kp&lt;sub&gt;uu&lt;/sub&gt; (solid bars) and Kp for neutral, acidic (mainly ionised at pH 7.4) and basic drugs (mainly ionised at pH 7.4). Data replotted from Mateus et al. (11) &lt;i&gt;In&lt;/i&gt; vivo, protein binding and free fraction have no effect on free drug concentration for oral drugs at steady-state. For oral drugs, intrinsic clearance is the key determinant of free drug concentrations in plasma and tissues. &lt;i&gt;In vitro&lt;/i&gt; potency assays represent a closed, static system in which nonspecific binding determines the free drug concentration, and should be corrected for. The only reason to measure fraction unbound in plasma is to convert total plasma concentrations/parameters to free concentrati","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"183 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666619","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}

{"title":"Structure of Mycobacterial NDH-2 Bound to a 2-Mercapto-Quinazolinone Inhibitor","authors":"Yingke Liang, Stephanie A. Bueler, Gregory M. Cook, John L. Rubinstein","doi":"10.1021/acs.jmedchem.5c00049","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00049","url":null,"abstract":"Mycobacterial type II NADH dehydrogenase (NDH-2) is a promising drug target because of its central role in energy metabolism in <i>Mycobacterium tuberculosis</i> and other pathogens, and because it lacks a known mammalian homologue. To facilitate optimization of lead compounds, we used electron cryomicroscopy (cryo-EM) to determine the structure of NDH-2 from <i>Mycobacterium smegmatis</i>, a fast-growing nonpathogenic model for respiration in <i>M. tuberculosis</i>. The structure shows that active mycobacterial NDH-2 is dimeric, with an arrangement of monomers in the dimer that differs from the arrangement described for other prokaryotic NDH-2 dimers, instead resembling dimers formed by NDH-2 in the eukaryotes <i>Saccharomyces cerevisiae</i> and <i>Plasmodium falciparum</i>. A structure of the enzyme bound to a 2-mercapto-quinazolinone inhibitor shows that the compound interacts directly with the flavin adenine dinucleotide cofactor, blocking the menaquinone-reducing site. These results reveal structural elements of NDH-2 that could be used to design specific inhibitors of the mycobacterial enzyme.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"41 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672654","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}

{"title":"Discovery of a Highly Potent and Selective Tyrosine Kinase 2 (TYK2) Degrader with In Vivo Therapeutic Efficacy in a Murine Psoriasis Model","authors":"Shuangshuang Xiong, Jiaqi Yang, Ming Yang, Maoxu Xiao, Si Ha, Wenxiang Tao, Luyu Ma, Chenxuan Ji, Hua Xiang, Guoshun Luo","doi":"10.1021/acs.jmedchem.5c00027","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00027","url":null,"abstract":"Tyrosine kinase 2 (TYK2), a critical scaffolding kinase required for type I interferon, IL-12 and IL-23 cytokine signaling, represents a compelling therapeutic target for various autoimmune diseases. However, existing TYK2 inhibitors only modulate its kinase activity. Here, we report the development of a first series of CRBN-recruiting TYK2 PROTACs based on an allosteric TYK2 inhibitor. Optimization of the potency and metabolic stability identified <b>15t</b> as an exceptionally potent and selective TYK2 degrader with a DC₅₀ value of 0.42 nM and a <i>D</i>_max value of 95%, which potently and selectively blocked TYK2-dependent signaling. Importantly, <b>15t</b> was active in vivo and significantly suppressed TYK2-mediated pathology in a murine psoriasis model without apparent toxicity. Collectively, our study provides a potentially valuable chemical knockdown probe for subtype-selective TYK2 degradation and further understanding TYK2 scaffolding biology, demonstrating the therapeutic potential of TYK2 PROTACs in immuno-inflammatory diseases such as psoriasis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666766","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}

{"title":"A New Protractor Potentiates Glucagon-Like Peptide 1 with Slow-Release Depot and Long-Term Action","authors":"Weina Jing, Lei Peng, Shiwei Song, Jiaqi Liu, Wanyi Tai","doi":"10.1021/acs.jmedchem.4c02970","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02970","url":null,"abstract":"Bioactive peptides display a number of favorable features as therapeutics, but their usage is challenging due to the low metabolic stability and rapid renal clearance. The small-molecule protractor, which functions by the noncovalent binding with serum albumin and protection against systemic clearance, is an attractive tool to elongate peptides’ half-life. Herein, we investigated coomassie brilliant blue (CBB) as a new protractor for the half-life extension of clinically relevant glucagon-like peptide 1 (GLP-1). A series of GLP-1 analogues differentiating with CBB linkers and acylation positions are described. One particularly interesting analogue (coomatide 13) exhibits sub-picomolar potency in vitro and long-term control of glucose homeostasis in mice. A protraction mechanism study reveals that CBB has a high affinity to albumin and pan-interaction with other matrix proteins, enabling to protract peptides in both systemic circulation and the subcutaneous depot. Our study demonstrates that the specific affinity to albumin is not a prerequisite for peptide protraction, and pan-binders might be advantageous.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672652","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}

{"title":"Rezatapopt (PC14586): A First-in-Class Small Molecule p53 Y220C Mutant Protein Stabilizer in Clinical Trials","authors":"Zonghui Ma, Qiang Shen, Jia Zhou","doi":"10.1021/acs.jmedchem.5c00670","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00670","url":null,"abstract":"The p53 protein, an important transcription factor, plays a critical role in regulating cell responses to stress. (1,2) Coded by the &lt;i&gt;TP&lt;/i&gt;53 gene, p53 is a well-recognized tumor suppressorprotein. Dysregulation of p53 function is closely associated with the initiation and development of various cancers. Although restoration of p53 function appears to be a promising therapeutic approach, p53 is considered to be a traditionally “undruggable” target owing to the lack of active binding pockets or frequent mutations. (3) Mutations in the &lt;i&gt;TP&lt;/i&gt;53 gene can assist tumor cells to evade p53 suppressive effects, promoting cell proliferation, migration, and invasion, thereby aggravating tumorigenesis. &lt;i&gt;TP&lt;/i&gt;53 genetic mutations present in more than 50% of human cancers, most of which are missense mutations occurring in the DNA-binding domain of p53 (amino acids 94–292). Y220C is the ninth most prevalent mutation among all &lt;i&gt;TP&lt;/i&gt;53 mutations observed across various tumor types, accounting for 1.8%, and presents in ∼1% of human cancers. (4) Y220C mutation leads to tyrosine-to-cysteine substitution and creates a pocket in the p53 Y220C mutant protein. p53 Y220C protein is structurally unstable at physiological temperatures and can be ubiquitinated and delivered to proteasomal for degradation. Therefore, targeting p53 Y220C-mutant stabilization may be a viable therapeutic strategy for various associated cancers. Small molecule compounds targeting p53 Y220C stabilization are in active development for potential cancer therapeutics. (5) Rezatapopt (PC14586), discovered by PMV Pharmaceuticals, Inc., is a first-in-class small molecule stabilizer and reactivator of p53 Y220C currently in the Phase II clinical trial (NCT04585750) for treating various locally advanced or metastatic solid tumors harboring a p53 Y220C mutation. (6) In addition, rezatapopt is in a Phase Ib clinical trial (NCT06616636) in combination with azacitidine for patients with &lt;i&gt;TP&lt;/i&gt;53 Y220C mutant myeloid malignancies (acute myeloid leukemia or myelodysplastic syndrome). Rezatapopt was designed to tightly occupy the pocket created by mutation-caused amino acid tyrosine-to-cysteine substitution in the p53 Y220C mutant protein. Rezatapopt was obtained based on structure-based drug design (SBDD) and systematical structural optimization, starting from hit compound &lt;b&gt;1&lt;/b&gt; (Figure 1). The substrate concentration required to increase DNA binding by 1.5-fold (SC&lt;sub&gt;150&lt;/sub&gt;) was determined by a time-resolved fluorescence resonance energy transfer (FRET) assay to assess the &lt;i&gt;in vitro&lt;/i&gt; potency of the p53 Y220C reactivators. Hit compound &lt;b&gt;1&lt;/b&gt; was obtained by scaffold combination of hit compounds PhiKan83 (SC&lt;sub&gt;150&lt;/sub&gt; = 37.2 μM) with a carbazole scaffold (7) and PK1596 (SC&lt;sub&gt;150&lt;/sub&gt; = 1.6 μM) with an iodophenol scaffold. (8) Compound &lt;b&gt;1&lt;/b&gt; contains a widely recognized “privileged” indole scaffold in drug development, which exists in numerous natural products and bioact","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"183 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660737","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}

{"title":"Chemoproteomic Profiling of C. albicans for Characterization of Antifungal Kinase Inhibitors","authors":"David J. Shirley, Meganathan Nandakumar, Aurora Cabrera, Bonnie Yiu, Emily Puumala, Zhongle Liu, Nicole Robbins, Luke Whitesell, Jeffrey L. Smith, Scott Lyons, Angie L. Mordant, Laura E. Herring, Lee M. Graves, Rafael M. Couñago, David H. Drewry, Leah E. Cowen, Timothy M. Willson","doi":"10.1021/acs.jmedchem.5c00097","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00097","url":null,"abstract":"<i>Candida albicans</i> is a major cause of systemic candidiasis, a severe fungal infection with a ∼40% mortality rate. Yck2, a casein kinase 1 (CK1) in <i>C. albicans</i>, is targeted by antifungal inhibitors YK-I-02 (YK) and MN-I-157 (MN). Using multiplexed inhibitor beads and mass spectrometry (MIB/MS), the selectivity of these inhibitors was determined across the fungal kinome. The MIB matrix captured 89% of <i>C. albicans</i> protein kinases, revealing that YK and MN selectively engage three CK1 homologues (Yck2, Yck22, and Hrr25) and a human p38α homologue (Hog1). Chemoproteomics using a custom MN-kinobead confirmed the remarkable fungal kinome selectivity. To identify new Yck2 inhibitors with selectivity over Hog1, 13 human CK1 inhibitors were screened, leading to the discovery of a new chemotype with antifungal activity. These findings highlight the utility of MIB/MS in profiling nonhuman kinomes and developing selective fungal kinase inhibitors as antimicrobial agents.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"26 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660743","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}

{"title":"Methyls and Me","authors":"Stuart Shapiro","doi":"10.1021/acs.jmedchem.5c00755","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00755","url":null,"abstract":"Like Proust’s famous encounter with a tasty madeleine, my encounter with the recent paper by Gerstenberger et al. (1) triggered memories of a longstanding romance with methyl moieties, my professional career having been flanked by projects focusing on methyl groups. My master’s studies at the University of Illinois at Urbana–Champaign dealt with the methanogenic dissimilation of methanol (and methylamine) by the archaeon &lt;i&gt;Methanosarcina barkeri&lt;/i&gt;, (2) and my doctoral studies at the Worcester Foundation for Experimental Biology, Inc. (Shrewsbury, MA) centered on biohydroxylation reactions at chiral methyl moieties. (3) Some four decades later my encounter with a strategically placed methyl group led to the creation of a pharmaceutical startup and invention of a new and exciting antibacterial drug. Most of my working life has been dedicated to applied microbiological research. Gerstenberger et al.’s publication on the nearly 400-fold improvement in potency observed for a &lt;i&gt;cis&lt;/i&gt;-2-methylcyclohexanamine derivative compared to that of the unmethylated congener reminded me of some examples of the value of methylation on the potency of antibacterial products, a subject barely addressed in reviews of methylation effects in medicinal chemistry published during the past 15 years. (4) Coumarins are a class of antibacterial compounds biosynthesized by streptomycetes. The only coumarin antibiotic to have been commercialized is novobiocin, which was used to treat staphylococcal infections until its withdrawal from the market during the 1980s due to safety and efficacy concerns. (5) Nonetheless, interest in antibacterial coumarins persists. (6) In their study of 3-aryl-6-nitrocoumarins, Matos et al. (7) reported that replacement of a hydrogen atom by a methyl group at the &lt;i&gt;meta&lt;/i&gt; position of the aryl moiety produced an increase (≥2 log&lt;sub&gt;2&lt;/sub&gt; dilution steps) in &lt;i&gt;in vitro&lt;/i&gt; activity toward &lt;i&gt;Staphylococcus aureus&lt;/i&gt;, though the reason for this enhanced antibacterial activity by &lt;i&gt;meta&lt;/i&gt;-methylation was not explored. Quinolones are synthetic broad-spectrum antibiotics suitable for outpatient use due to their high bioavailability. Most members of this antibiotic family contain a fluorine atom at position 6, following Koga et al.’s report (8) that the presence of a fluorine atom at C-6 of the quinolone pharmacophore improved antimicrobial activity and oral bioavailability. One such fluoroquinolone, ciprofloxacin, featured prominently as a treatment for exposure to &lt;i&gt;Bacillus anthracis&lt;/i&gt; spores during the anthrax scare following the 9/11 terrorist attacks on the New York City World Trade Center towers. (9) For several decades invention of new (fluoro)quinolones was actively pursued by diverse pharmaceutical houses, especially Bayer AG (Wuppertal, Germany) and Wakunaga Pharmaceutical Co. (Hiroshima, Japan). Chemists at the latter firm invented delafloxacin (Baxdela), the last fluoroquinolone to have been approved by the United States Food","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666770","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}

{"title":"Discovery of Novel SIK2/3 Inhibitors for the Potential Treatment of MEF2C+ Acute Myeloid Leukemia (AML)","authors":"Wei Zhu, Pei Zhao, Tingting Liu, Feng Gao, Qi Li, Xin Cai, Man Zhang, Alex Aliper, Feng Ren, Alex Zhavoronkov, Xiao Ding","doi":"10.1021/acs.jmedchem.4c03225","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03225","url":null,"abstract":"The dual inhibition of SIK2/3 has been considered as a potential treatment approach for MEF2C-high acute myeloid leukemia (AML). Although diverse scaffolds of pan-SIK or SIK2/3 inhibitors have been reported, few of them showed sufficient in vitro or in vivo antitumor activity. Based on the proposed binding mode of the hit molecule (<b>7</b>), chemical space in the solvent/P-loop region was explored via fragment growing/replacement, supported by the generative chemistry platform. Further SAR exploration and ADME optimization led to the discovery of <b>7s</b>, which exhibited excellent potency and strong selectivity in MEF2C high-expression cell lines over MEF2C-low cell lines. Moreover, oral administration of <b>7s</b> was found to demonstrate significant tumor growth inhibition in a MV4-11 AML mice CDX model without any body weight loss. This work highlights the potential of targeting MEF2C-dependent AML by selective oral SIK2/3 inhibitors, which was supported by the generative models.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660739","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}