Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors

Communications Chemistry, Год журнала: 2024, Номер 7(1)

Опубликована: Фев. 20, 2024

Abstract Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to dual motif architecture these variability that can be introduced differing linker structures geometries. We report a set alternatively linked EGFR simultaneously occupy ATP substrate allosteric pockets. Crystal show initial redesigned trisubstituted imidazole ATP-site inhibitor dibenzodiazepinone allosteric-site proved successful in spanning sites. The re-engineered yielded compound exhibited significantly higher potency (~60 pM) against drug-resistant L858R/T790M L858R/T790M/C797S, which was superadditive as compared parent molecules. enhanced attributed factors stemming from connection group informs strategies engineer agent design.

Язык: Английский

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Innovative, combinatorial and high-throughput approaches to degrader synthesis

Chemical Society Reviews, Год журнала: 2024, Номер 53(10), С. 4838 - 4861

Опубликована: Янв. 1, 2024

In this review we highlight how the synthesis of degraders has evolved in recent years, particular application high-throughput chemistry and screening approaches such as D2B DEL technologies to expedite discovery timelines.

Язык: Английский

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Discovery of SMD-3236: A Potent, Highly Selective and Efficacious SMARCA2 Degrader for the Treatment of SMARC4-Deficient Human Cancers

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 2, 2025

SMARCA2 is an attractive synthetic lethal target in human cancers with mutated, inactivated SMARCA4. We report herein the discovery of highly potent and selective PROTAC degraders, as exemplified by SMD-3236, which was designed using a new, high-affinity SMARCA ligand VHL-1 ligand. SMD-3236 achieves DC

Язык: Английский

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Targeted Covalent Modification Strategies for Drugging the Undruggable Targets

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

The term "undruggable" refers to proteins or other biological targets that have been historically challenging target with conventional drugs therapeutic strategies because of their structural, functional, dynamic properties. Drugging such undruggable is essential develop new therapies for diseases where current treatment options are limited nonexistent. Thus, investigating methods achieve drugging an important challenge in medicinal chemistry. Among the numerous methodologies drug discovery, covalent modification has emerged as a transformative strategy. attachment diverse functional molecules provides powerful platform creating highly potent and chemical tools well ability provide valuable information on structures dynamics targets. In this review, we summarize recent examples biomolecules development therapeutics overcome discovery challenges highlight how contribute toward particular, focus use chemistry drugs, identification, screening, artificial modulation post-translational modifications, cancer specific chemotherapies, nucleic acid-based therapeutics.

Язык: Английский

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Modulating the phosphorylation status of target proteins through bifunctional molecules

Drug Discovery Today, Год журнала: 2025, Номер unknown, С. 104307 - 104307

Опубликована: Фев. 1, 2025

Язык: Английский

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Rezatapopt (PC14586): A First-in-Class Small Molecule p53 Y220C Mutant Protein Stabilizer in Clinical Trials

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 20, 2025

InfoMetricsFiguresRef.SI Journal of Medicinal ChemistryASAPArticle This publication is free to access through this site. Learn More CiteCitationCitation and abstractCitation referencesMore citation options ShareShare onFacebookXWeChatLinkedInRedditEmailBlueskyJump toExpandCollapse EditorialMarch 20, 2025Rezatapopt (PC14586): A First-in-Class Small Molecule p53 Y220C Mutant Protein Stabilizer in Clinical TrialsClick copy article linkArticle link copied!Zonghui MaZonghui MaChemical Biology Program, Department Pharmacology Toxicology, University Texas Medical Branch (UTMB), Galveston, 77555, United StatesMore by Zonghui Mahttps://orcid.org/0000-0002-4265-9319Qiang ShenQiang ShenDepartment Interdisciplinary Oncology, School Medicine, LSU LCMC Health Cancer Center, Louisiana State Sciences New Orleans, 70112, Qiang ShenJia Zhou*Jia ZhouChemical States*Dr. Jia Zhou. Phone: 409-772-9748; E-mail: [email protected]More Zhouhttps://orcid.org/0000-0002-2811-1090Open PDFJournal ChemistryCite this: J. Med. Chem. 2025, XXXX, XXX, XXX-XXXClick citationCitation copied!https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c00670https://doi.org/10.1021/acs.jmedchem.5c00670Published March 2025 Publication History Received 6 2025Published online 20 2025editorialPublished American Chemical Society. available under these Terms Use. Request reuse permissionsThis licensed for personal use The ACS PublicationsPublished SocietyThe protein, an important transcription factor, plays a critical role regulating cell responses stress. (1,2) Coded the TP53 gene, well-recognized tumor suppressorprotein. Dysregulation function closely associated with initiation development various cancers. Although restoration appears be promising therapeutic approach, considered traditionally "undruggable" target owing lack active binding pockets or frequent mutations. (3) Mutations gene can assist cells evade suppressive effects, promoting proliferation, migration, invasion, thereby aggravating tumorigenesis. genetic mutations present more than 50% human cancers, most which are missense occurring DNA-binding domain (amino acids 94–292). ninth prevalent mutation among all observed across types, accounting 1.8%, presents ∼1% (4) leads tyrosine-to-cysteine substitution creates pocket mutant protein. protein structurally unstable at physiological temperatures ubiquitinated delivered proteasomal degradation. Therefore, targeting Y220C-mutant stabilization may viable strategy molecule compounds potential cancer therapeutics. (5)Rezatapopt (PC14586), discovered PMV Pharmaceuticals, Inc., first-in-class small stabilizer reactivator currently Phase II clinical trial (NCT04585750) treating locally advanced metastatic solid tumors harboring mutation. (6) In addition, rezatapopt Ib (NCT06616636) combination azacitidine patients myeloid malignancies (acute leukemia myelodysplastic syndrome). Rezatapopt was designed tightly occupy created mutation-caused amino acid obtained based on structure-based drug design (SBDD) systematical structural optimization, starting from hit compound 1 (Figure 1). substrate concentration required increase DNA 1.5-fold (SC150) determined time-resolved fluorescence resonance energy transfer (FRET) assay assess vitro potency reactivators. Hit scaffold PhiKan83 (SC150 = 37.2 μM) carbazole (7) PK1596 1.6 iodophenol scaffold. (8) Compound contains widely recognized "privileged" indole development, exists numerous natural products bioactive molecules. has three anchors attached scaffold, including hydrophobic ethyl group, polar alkylamine extending solvent region, substituted acetylene occupying adjacent subsite. 13.6 showed inadequate > 100 nM) poor metabolic stability liver microsome (T1/2 4 min). SBDD efforts around resulted lead 2 (PC-9859) significantly improved activity 54 nM). cocrystal structure (PDB code: 9BR4) complex 2, revealed that locates space Trifluoromethyl group inserts deeply into pocket, 4-aminopiperidine ring extends toward solvent-exposed pyridine connected core via alkyne occupies forms favorable CH-π stacking interaction Pro153. two key hydrogen bonds One formed between carbonyl Cys220 while other 1-methylpiperidine Thr150 side chain. Further optimization successfully led discovery fluorine atom piperidine amide phenyl projected region.Figure 1Figure 1. Drug Cocrystal complexed shown. shown as cartoon. Hydrogen residues within water molecules highlighted red dashed lines. green sticks. Key Cys220, Thr150, Pro153 yellow Water balls.High Resolution ImageDownload MS PowerPoint SlideAs optimal reactivator, binds similar mode stabilizes its wide-type (WT) conformation, restoring functions. introduction further strengthened increased bond enhanced conformational rigidity ring, reduced basicity. Moreover, chiral conformation fluorine-substituted obvious effect 3S,4R configuration optimal. Furthermore, remarkably pharmacokinetic (PK) profiles. increases 9 it potently suppresses growth NUGC-3 (a gastric line mutation) IC50 value 504 nM, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. (po, 50 mg/kg) displays desirable PK profiles mouse (Cmax 16600 ng/mL AUC0-last 163342 ng.h/mL). Excitingly, QD) doses both 25 mg/kg mg/kg, robustly xenograft model (TGI 33% 71%, respectively). causes significant suppression higher dose resulting impressive 80% regression. Notably, toxicological studies, safety profile. Given potent vivo efficacy well profiles, trials. I (NCT04585750), displayed profile efficacious doses. (9) rezatapopt, monotherapy, produced robust heavily pretreated multiple types (NCT04585750, https://clinicaltrials.gov) recruiting, serving registrational study investigate safety, tolerability monotherapy participants some cases, destabilization root cause several classes diseases, proteins (e.g., p53, p21, p57, FOXO3A, IRF3 BAX), mutated misfolded proteins, such ΔF508-cystic fibrosis transmembrane conductance regulator (ΔF508-CFTR) cystic fibrosis, glucokinase pancreatic maturity-onset diabetes young type (MODY2), transthyretin (TTR) cardiac amyloidosis (ATTR-CM). (10) (TPS) rather degradation (TPD) would therapeutically beneficial. TPS attracting increasing attention researchers academic industrial settings stabilizers have been developed. Inspiringly, TTR stabilizers, tafamidis developed Pfizer acoramidis Stanford University, had approved U.S. FDA ATTR-CM 2019 2024 respectively. (11) emergence trial, represents great breakthrough field "undruggable also provides basis developing p53-based chemical inducers proximity (CIPs). Besides monovalent heterobifunctional (CIPs) developed, deubiquitinase-targeting chimeras (DUBTACs), (12) RESTORACs, enhancement-targeting (ENTACs). Biotech companies Vicinitas, Stablix, Entact Bio centering DUBTACs, RESTORACs ENTACs, (13) With continued efforts, anticipated candidates, conferring benefits.In summary, exciting restoration. Like drugs KRAS G12C, shows convert "druggable" target. phase benefiting results will achieved released near future.Author InformationClick section linkSection copied!Corresponding AuthorJia Zhou, States, https://orcid.org/0000-0002-2811-1090, Email: protected]AuthorsZonghui Ma, https://orcid.org/0000-0002-4265-9319Qiang Shen, StatesNotesViews expressed editorial those authors not necessarily views ACS.The declare no competing financial interest.AcknowledgmentsClick copied!This work partially supported R01CA226001 R01CA231150 grants National Institutes Health, Breast Research Program (BCRP) Breakthrough Awards W81XWH-17-1-0071 W81XWH-17-1-0072 Defense (DoD), John D. Stobo, M.D. Distinguished Chair Endowment, Edith & Robert Zinn Endowment Discovery.ReferencesClick copied! references 13 publications. 1Vogelstein, B.; Lane, D.; Levine, A. Surfing network. Nature 2000, 408, 307– 310, DOI: 10.1038/35042675 Google Scholar1Surfing networkVogelstein, Bert; David; Arnold J.Nature (London) (2000), 408 (6810), 307-310CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group) There expanded reference. >> SciFinder ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXosVemtrY%253D&md5=136728653fb9e30f8ac0c48bf7701a082Harris, S. L.; pathway: positive negative feedback loops. Oncogene 2005, 24, 2899– 2908, 10.1038/sj.onc.1208615 Scholar2The loopsHarris, Sandra J.Oncogene (2005), 24 (17), 2899-2908CODEN: ONCNES; ISSN:0950-9232. review. pathway responds stresses disrupt fidelity replication division. stress signal transmitted post-translational modifications. activation factor initiates program cycle arrest, cellular senescence apoptosis. transcriptional network p53-responsive genes produces interact large no. transduction pathways pos. neg. autoregulatory loops act upon response. least seven described here, these, six MDM-2 regulate activity. circuit communicates Wnt-beta-catenin, IGF-1-AKT, Rb-E2F, p38 MAP kinase, cyclin-cdk, p14/19 ARF cyclin G-PP2A, p73 products. different ubiquitin ligases manner: MDM-2, Cop-1 Pirh-2. meaning redundancy relative each stages remains elucidated. interconnections play central our understanding cancer. ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjtlehs7c%253D&md5=67d06ba0e28c4afdac85172ea2970e493Hassin, O.; Oren, M. Drugging cancer: one many targets. Nat. Rev. Discov. 2023, 22, 127– 144, 10.1038/s41573-022-00571-8 ScholarThere corresponding record reference.4Bouaoun, Sonkin, Ardin, M.; Hollstein, Byrnes, G.; Zavadil, J.; Olivier, Variations Human Cancers: Lessons IARC Database Genomics Data. Hum. Mutat. 2016, 37, 865– 876, 10.1002/humu.23035 Scholar4TP53 DataBouaoun, Liacine; Dmitriy; Maude; Monica; Graham; Jiri; MagaliHuman Mutation (2016), 37 (9), 865-876CODEN: HUMUE3; ISSN:1059-7794. (Wiley-Liss, Inc.) somatic events () popular resource compiles occurrence phenotype data germline variations linked deluge coming genomic studies generates new attracts growing database users interpretation variants. Here, we current contents functionalities perform systematic anal. extd. repositories. repositories (29,000 vs. 4,000). However, complete screening overlooked facts about mutations, presence outside specific types. We provide update inherited variants ones should neutral variations. thus knowledge inform efficient Database. ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhtlansb7E&md5=0ba89e839266283880ab9d8011669b945Joerger, C.; Ang, H. Fersht, R. Structural oncogenic designing rescue drugs. Proc. Natl. Acad. Sci. U. 2006, 103, 15056– 15061, 10.1073/pnas.0607286103 Scholar5Structural drugsJoerger, Andreas Hwee Ching; Alan R.Proceedings Academy States America (2006), 103 (41), 15056-15061CODEN: PNASA6; ISSN:0027-8424. (National Sciences) suppressor inactivated ≈50% solved high-resoln. crystal structures mutants inactivation information mutants. found variety consequences mutation: (i) removal essential contact DNA, (ii) creation large, water-accessible crevices internal cavities changes but loss thermodn. stability, (iii) distortion surface, (iv) alterations surfaces directly involved domain-domain interactions tetramer. These findings explain differences functional properties assocd. phenotypes temp. sensitivity). Some being rescued generic stabilizing drug. addn., mutation-induced crevice site mutant-selective ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFais7zE&md5=62916fd1558d6bf3e941201756c433036Vu, B. T.; Dominique, R.; Fahr, Li, H.; Fry, Xu, Yang, Puzio-Kuter, A.; Good, Liu, Huang, K. S.; Tanaka, N.; Davis, T. W.; Dumble, L. Discovery First-in-Class, Small-Molecule Reactivator Development. Lett. 16, 34– 39, 10.1021/acsmedchemlett.4c00379 reference.7Boeckler, F. Joerger, Jaggi, Rutherford, Veprintsev, Targeted destabilized silico screened 2008, 105, 10360– 10365, 10.1073/pnas.0805326105 Scholar7Targeted drugBoeckler, Frank Gaurav; Trevor Dmitry (2008), 105 (30), 10360-10365CODEN: mutationally Approx. one-third lower melting leading rapid denaturation. mols. bind stabilize them could effective anticancer Y220C, occurs ≈75,000 cases per annum, surface cavity destabilizes kcal/mol, functional. series using virtual rational design. them, deriv. (PhiKanO83), dissocn. const. ≈150 μM. It raises slows down rate protein-PhiKanO83 1.5-Å resoln. implicates ligand occur binding, optimization. excellent testing novel stabilization. point out general principles relationships consts., raising temps., half-lives ligands. ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpsFKktL0%253D&md5=a6d8305c1f019e83d7b033885005ffd98Wilcken, X.; Zimmermann, Boeckler, Halogen-enriched fragment libraries p53. Am. Soc. 2012, 134, 6810– 6818, 10.1021/ja301056a Scholar8Halogen-Enriched Fragment Libraries Leads Rescue p53Wilcken, Rainer; Xiangrui; Markus M.Journal Society (2012), 134 (15), 6810-6818CODEN: JACSAT; ISSN:0002-7863. (American Society) destabilizing druggable crevice. exploiting halogen bonding halogen-enriched (HEFLibs) points complement classical approaches. From HEFLibs subsequent structure-guided design, 2-(aminomethyl)-4-ethynyl-6-iodophenols p53-Y220C stabilizers. Crystal their complexes highlight features: anchored iodine main-chain linker, enabling addnl. subsite best binders induction apoptosis homozygous Our biophys. suggest widespread applicability discovery. ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XksVKnsb0%253D&md5=0b2a07f8c4e3fef83789d854ade41e719Puzio-Kuter, McBrayer, K.; Brown, Wiebesiek, E.; Russo, Mulligan, C. Battaglia, Robell, Thomas, Solovyov, Greenbaum, Oliner, Johnson, Xiong, P.; Lozano, Fellous, Vu, Schram, Poyurovsky, V. Restoration Tumor Suppressor Function Y220C-Mutant Rezatapopt, Reactivator. 10.1158/2159-8290.CD-24-1421 reference.10Liu, Ciulli, Proximity-Based Modalities Medicine. Cent. 9, 1269– 1284, 10.1021/acscentsci.3c00395 reference.11Mullard, approves second amyloidosis. 6, 10.1038/d41573-024-00188-z reference.12Ma, Z.; Chen, Q.; Deubiquitinase-Targeting Chimeras (DUBTACs) Potential Paradigm-Shifting Approach. press. 10.1021/acs.jmedchem.4c02975 .Google reference.13Mullard, Proximity-inducing get closer. 254– 257, 10.1038/d41573-023-00044-6 reference.Cited By Click yet cited publications.Download PDFFiguresReferencesSupporting Information Get e-AlertsGet e-AlertsJournal copied!https://doi.org/10.1021/acs.jmedchem.5c00670Published permissionsArticle Views-Altmetric-Citations-Learn metrics closeArticle Views COUNTER-compliant sum full text downloads since November 2008 (both PDF HTML) institutions individuals. regularly updated reflect usage up last few days.Citations number articles citing article, calculated Crossref daily. Find counts.The Altmetric Attention Score quantitative measure research received online. Clicking donut icon load page altmetric.com additional details score social media given article. how calculated.Recommended Articles FiguresReferencesSupporting InfoFigure SlideReferences 1Surfing 2The 4TP53 5Structural 7Targeted 8Halogen-Enriched .There reference.PDB: 9BR4

Язык: Английский

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The expanding repertoire of covalent warheads for drug discovery

Drug Discovery Today, Год журнала: 2023, Номер 28(12), С. 103799 - 103799

Опубликована: Окт. 13, 2023

Язык: Английский

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Integrated Direct-to-Biology Platform for the Nanoscale Synthesis and Biological Evaluation of PROTACs

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(22), С. 15437 - 15452

Опубликована: Ноя. 7, 2023

Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that co-opt the cell's natural proteasomal degradation mechanisms to degrade undesired proteins. A challenge associated with PROTACs is time and resource-intensive optimization; thus, development of high-throughput platforms for their synthesis biological evaluation required. In this study, we establish an ultra-high-throughput experimentation (ultraHTE) platform PROTAC synthesis, followed by direct addition crude reaction mixtures cellular assays without any purification. This 'direct-to-biology' (D2B) approach was validated then exemplified in a medicinal chemistry campaign identify novel BRD4 PROTACs. Using D2B platform, 650 carried out 1536-well plate, subsequent performed single scientist less than 1 month. Due its ability hugely accelerate optimization new degraders, anticipate our will transform testing

Язык: Английский

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Accelerating PROTACs Discovery Through a Direct‐to‐Biology Platform Enabled by Modular Photoclick Chemistry

Advanced Science, Год журнала: 2024, Номер 11(26)

Опубликована: Апрель 30, 2024

Abstract Proteolysis targeting chimeras (PROTACs) have emerged as a promising strategy for drug discovery and exploring protein functions, offering revolutionary therapeutic modality. Currently, the predominant approach to PROTACs mainly relies on an empirical design–synthesis–evaluation process involving numerous cycles of labor‐intensive synthesis‐purification bioassay data collection. Therefore, development innovative methods expedite PROTAC synthesis exploration chemical space remains highly desired. Here, direct‐to‐biology is reported streamline libraries plates, enabling seamless transfer reaction products cell‐based bioassays without need additional purification. By integrating amide coupling light‐induced primary amines o‐nitrobenzyl alcohols cyclization (PANAC) photoclick chemistry into plate‐based synthetic process, this produces with high efficiency structural diversity. Moreover, by employing platform screening, we smoothly found potent effectively inhibit triple‐negative breast cancer (TNBC) cell growth induce rapid, selective targeted degradation cyclin‐dependent kinase 9 (CDK9). The study introduces versatile assembling followed direct biological evaluation. This provides opportunity high‐throughput libraries, thereby enhancing accelerating PROTACs.

Язык: Английский

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An updated patent review of BRD4 degraders

Expert Opinion on Therapeutic Patents, Год журнала: 2024, Номер 34(10), С. 929 - 951

Опубликована: Сен. 2, 2024

Bromodomain-containing protein 4 (BRD4), an important epigenetic reader, is closely associated with the pathogenesis and development of many diseases, including various cancers, inflammation, infectious diseases. Targeting BRD4 inhibition or elimination small molecules represents a promising therapeutic strategy, particularly for cancer therapy.

Язык: Английский

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