{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T11:06:13Z","timestamp":1773659173063,"version":"3.50.1"},"reference-count":36,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Bioorganic & Medicinal Chemistry"],"published-print":{"date-parts":[[2025,3]]},"DOI":"10.1016\/j.bmc.2025.118079","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T01:00:34Z","timestamp":1737507634000},"page":"118079","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":7,"special_numbering":"C","title":["Design, Synthesis, and biological evaluation of 7H-Pyrrolo[2,3-d]pyrimidines as potent HPK1 kinase inhibitors"],"prefix":"10.1016","volume":"119","author":[{"given":"Feifei","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiqiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laishun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"An","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaqi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaoliang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinghua","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingxing","family":"Diao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linghua","family":"Meng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0845-0260","authenticated-orcid":false,"given":"Shilin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.bmc.2025.118079_b0005","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/s41568-021-00347-z","article-title":"Systemic immunity in cancer","volume":"21","author":"Hiam-Galvez","year":"2021","journal-title":"Nature Reviews. Cancer"},{"key":"10.1016\/j.bmc.2025.118079_b0010","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1016\/j.cell.2023.03.006","article-title":"Immune checkpoint therapy\u2014current perspectives and future directions","volume":"186","author":"Sharma","year":"2023","journal-title":"Cell"},{"key":"10.1016\/j.bmc.2025.118079_b0015","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.3390\/cancers11111756","article-title":"Targeting Negative and Positive Immune Checkpoints with Monoclonal Antibodies in Therapy of Cancer","volume":"11","author":"Marhelava","year":"2019","journal-title":"Cancers (Basel)"},{"key":"10.1016\/j.bmc.2025.118079_b0020","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.celrep.2018.09.012","article-title":"The Kinase Activity of Hematopoietic Progenitor Kinase 1 Is Essential for the Regulation of T Cell Function","volume":"25","author":"Hernandez","year":"2018","journal-title":"Cell Reports"},{"key":"10.1016\/j.bmc.2025.118079_b0025","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/bs.ai.2015.09.006","article-title":"MAP4K Family Kinases in Immunity and Inflammation","volume":"129","author":"Chuang","year":"2016","journal-title":"Advances in Immunology"},{"key":"10.1016\/j.bmc.2025.118079_b0030","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.55122","article-title":"A perspective on HPK1 as a novel immuno-oncology drug target","volume":"9","author":"Sawasdikosol","year":"2020","journal-title":"eLife"},{"key":"10.1016\/j.bmc.2025.118079_b0035","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1128\/MCB.25.6.2364-2383.2005","article-title":"Activation of hematopoietic progenitor kinase 1 involves relocation, autophosphorylation, and transphosphorylation by protein kinase D1","volume":"25","author":"Arnold","year":"2005","journal-title":"Molecular Cell. Biology"},{"key":"10.1016\/j.bmc.2025.118079_b0040","article-title":"Serine Phosphorylation of SLP76 Is Dispensable for T Cell Development but Modulates Helper T Cell Function","volume":"12","author":"Navas","year":"2017","journal-title":"PLoS One1"},{"key":"10.1016\/j.bmc.2025.118079_b0045","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1084\/jem.20062066","article-title":"A novel pathway down-modulating T cell activation involves HPK-1-dependent recruitment of 14-3-3 proteins on SLP-76","volume":"204","author":"Di Bartolo","year":"2007","journal-title":"The Journal of Experimental Medicine"},{"key":"10.1016\/j.bmc.2025.118079_b0050","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.ccell.2020.08.001","article-title":"Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies","volume":"38","author":"Si","year":"2020","journal-title":"Cancer Cell"},{"key":"10.1016\/j.bmc.2025.118079_b0055","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-001402","article-title":"Enhanced antitumor immunity by a novel small molecule HPK1 inhibitor","volume":"9","author":"You","year":"2021","journal-title":"Journal for Immunotherapy of Cancer"},{"key":"10.1016\/j.bmc.2025.118079_b0060","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1021\/acs.jmedchem.2c01551","article-title":"Discovery of Macrocycle-Based HPK1 Inhibitors for T-Cell-Based Immunotherapy","volume":"66","author":"Wang","year":"2023","journal-title":"Journal of Medicinal Chemistry"},{"key":"10.1016\/j.bmc.2025.118079_b0065","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2024.116206","article-title":"Discovery of novel, potent, selective and orally bioavailable HPK1 inhibitor for enhancing the efficacy of anti-PD-L1 antibody","volume":"267","author":"Zeng","year":"2024","journal-title":"European Journal of Medicinal Chemistry"},{"key":"10.1016\/j.bmc.2025.118079_b0070","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1021\/acsmedchemlett.1c00096","article-title":"Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds","volume":"12","author":"Vara","year":"2021","journal-title":"ACS Medicinal Chemistry Letters"},{"key":"10.1016\/j.bmc.2025.118079_b0075","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1021\/acsmedchemlett.1c00473","article-title":"Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1)","volume":"13","author":"Chan","year":"2021","journal-title":"ACS Medicinal Chemistry Letters"},{"key":"10.1016\/j.bmc.2025.118079_b0080","doi-asserted-by":"crossref","first-page":"4888","DOI":"10.1021\/acs.jmedchem.2c02038","article-title":"Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1","volume":"66","author":"Gallego","year":"2023","journal-title":"Journal of Medicinal Chemistry"},{"key":"10.1016\/j.bmc.2025.118079_b0085","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2022.115064","article-title":"Development of a series of quinazoline-2,5-diamine derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors","volume":"248","author":"Shi","year":"2023","journal-title":"European Journal of Medicinal Chemistry"},{"key":"10.1016\/j.bmc.2025.118079_b0090","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1021\/acsmedchemlett.0c00660","article-title":"Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1","volume":"12","author":"Degnan","year":"2021","journal-title":"ACS Medicinal Chemistry Letters"},{"key":"10.1016\/j.bmc.2025.118079_b0095","doi-asserted-by":"crossref","DOI":"10.1021\/acschembio.1c00819","article-title":"The HPK1 Inhibitor A-745 Verifies the Potential of Modulating T Cell Kinase Signaling for Immunotherapy","author":"Malchow","year":"2022","journal-title":"ACS Chemical Biology"},{"key":"10.1016\/j.bmc.2025.118079_b0100","unstructured":"BGB-15025 Alone and in Combination with Anti-PD-1 Monoclonal Antibody Tislelizumab in Participants with Advanced Solid Tumors. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04649385 (accessed Nov 21, 2024)."},{"key":"10.1016\/j.bmc.2025.118079_b0105","unstructured":"PF-07265028 as Single Agent and in Combination with Sasanlimab in Advanced or Metastatic Solid Tumors. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05233436 (accessed Nov 26, 2024)."},{"key":"10.1016\/j.bmc.2025.118079_b0110","unstructured":"A Study of NDI 1150\u2013101 in Patients with Solid Tumors. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05128487 (accessed Nov 26, 2024)."},{"key":"10.1016\/j.bmc.2025.118079_b0115","unstructured":"A Study Investigating BGB-26808 Alone or in Combination with Tislelizumab in Participants with Advanced Solid Tumors. https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT05981703 (accessed Nov 21, 2024)."},{"key":"10.1016\/j.bmc.2025.118079_b0120","unstructured":"A Phase I\/II Study to Evaluate the Safety, Pharmacokinetics and Efficacy of PRJ1\u20133024 in Subjects with Advanced Solid Tumors. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05315167 (accessed Nov 21, 2024)."},{"key":"10.1016\/j.bmc.2025.118079_b0125","unstructured":"Safety and Efficacy Study of CFI-402411 in Subjects with Advanced Solid Malignancies. https:\/\/clinicaltrials.gov\/ct2\/show\/ NCT04521413 (accessed Nov 21, 2024)."},{"key":"10.1016\/j.bmc.2025.118079_b0130","unstructured":"A Phase I Study of RGT-264 in Subjects with Advanced Solid Tumors. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05764915 (accessed Nov 21, 2024)."},{"key":"10.1016\/j.bmc.2025.118079_b0135","unstructured":"A Study of GRC 54276 in Participants with Advanced Solid Tumors and Lymphomas. https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT05878691 (accessed Nov 21, 2024)."},{"key":"10.1016\/j.bmc.2025.118079_b0140","unstructured":"A Phase I\/II, Open-label Study to Investigate the Safety, Tolerability, PK, and Preliminary Efficacy of FB849. https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT05761223 (accessed Nov 21, 2024)."},{"key":"10.1016\/j.bmc.2025.118079_b0145","unstructured":"A Phase 1 Study of BB3008 in Participants With Advanced Solid Tumors. https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT06143007 (accessed Nov 21, 2024)."},{"key":"10.1016\/j.bmc.2025.118079_b0150","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2023.115355","article-title":"Discovery of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors","volume":"254","author":"Wu","year":"2023","journal-title":"European Journal of Medicinal Chemistry"},{"key":"10.1016\/j.bmc.2025.118079_b0155","unstructured":"M.P. Pollastri, Overview on the Rule of Five. Curr Protoc Pharmacol. 2010; Chapter 9 (1934-8290 (Electronic)): Unit 9.12."},{"key":"10.1016\/j.bmc.2025.118079_b0160","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.apsb.2018.04.003","article-title":"Drug metabolism in drug discovery and development","volume":"8","author":"Zhang","year":"2018","journal-title":"Acta Pharmaceutica Sinica B"},{"key":"10.1016\/j.bmc.2025.118079_b0165","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1021\/jm8008663","article-title":"Metabolic Soft Spot Identification and Compound Optimization in Early Discovery Phases Using MetaSite and LC-MS\/MS Validation","volume":"52","author":"Trunzer","year":"2009","journal-title":"Journal of Medicinal Chemistry"},{"key":"10.1016\/j.bmc.2025.118079_b0170","doi-asserted-by":"crossref","first-page":"8315","DOI":"10.1021\/acs.jmedchem.5b00258","article-title":"Applications of Fluorine in Medicinal Chemistry","volume":"58","author":"Gillis","year":"2015","journal-title":"Journal of Medicinal Chemistry"},{"key":"10.1016\/j.bmc.2025.118079_b0175","doi-asserted-by":"crossref","first-page":"5822","DOI":"10.1021\/acs.jmedchem.7b01788","article-title":"Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design","volume":"61","author":"Meanwell","year":"2018","journal-title":"Journal of Medicinal Chemistry"},{"key":"10.1016\/j.bmc.2025.118079_b0180","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1177\/2472555220952071","article-title":"Development of High-Throughput Assays for Evaluation of Hematopoietic Progenitor Kinase 1 Inhibitors","volume":"26","author":"Lacey","year":"2021","journal-title":"SLAS Discov."}],"container-title":["Bioorganic & Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0968089625000203?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0968089625000203?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T05:22:52Z","timestamp":1740460972000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0968089625000203"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3]]},"references-count":36,"alternative-id":["S0968089625000203"],"URL":"https:\/\/doi.org\/10.1016\/j.bmc.2025.118079","relation":{},"ISSN":["0968-0896"],"issn-type":[{"value":"0968-0896","type":"print"}],"subject":[],"published":{"date-parts":[[2025,3]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Design, Synthesis, and biological evaluation of 7H-Pyrrolo[2,3-d]pyrimidines as potent HPK1 kinase inhibitors","name":"articletitle","label":"Article Title"},{"value":"Bioorganic & Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bmc.2025.118079","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"118079"}}