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

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