Discovery of macrocyclic derivatives bearing N-sulfonyl-pyrazole moiety as new potent hematopoietic progenitor kinase 1 inhibitors.
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| Title: | Discovery of macrocyclic derivatives bearing N-sulfonyl-pyrazole moiety as new potent hematopoietic progenitor kinase 1 inhibitors. |
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| Authors: | Wang L; State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan, 430079, PR China., Li ZL; State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan, 430079, PR China. Electronic address: lizilong@mails.ccnu.edu.cn., Duan CX; State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan, 430079, PR China., Yang XQ; State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan, 430079, PR China., Wang HT; State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan, 430079, PR China., Gu XR; School of Pharmacy, Nanjing University of Chinese Medicine (Taizhou Campus), Taizhou, 225316, PR China., Wang GQ; State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan, 430079, PR China., Cheng QH; State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan, 430079, PR China., Wang MS; State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan, 430079, PR China., She NF; State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan, 430079, PR China. Electronic address: nfshe@mail.ccnu.edu.cn., Shi XX; State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan, 430079, PR China. Electronic address: xxshi@mails.ccnu.edu.cn., Huang W; State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan, 430079, PR China. Electronic address: weihuangwuhan@126.com. |
| Source: | Bioorganic chemistry [Bioorg Chem] 2025 Dec; Vol. 167, pp. 109196. Date of Electronic Publication: 2025 Nov 05. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Amsterdam : Elsevier Original Publication: New York, London, Academic Press. |
| MeSH Terms: | Pyrazoles*/chemistry , Pyrazoles*/pharmacology , Pyrazoles*/chemical synthesis , Protein Kinase Inhibitors*/pharmacology , Protein Kinase Inhibitors*/chemistry , Protein Kinase Inhibitors*/chemical synthesis , Antineoplastic Agents*/pharmacology , Antineoplastic Agents*/chemistry , Antineoplastic Agents*/chemical synthesis , Protein Serine-Threonine Kinases*/antagonists & inhibitors , Protein Serine-Threonine Kinases*/metabolism , Macrocyclic Compounds*/chemistry , Macrocyclic Compounds*/pharmacology , Macrocyclic Compounds*/chemical synthesis , Drug Discovery*, Humans ; Animals ; Mice ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Cell Proliferation/drug effects ; Microsomes, Liver/metabolism ; Cell Line, Tumor ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/pathology |
| Abstract: | Hematopoietic progenitor kinase 1 (HPK1), due to its crucial intracellular negative regulation of T-cell receptor (TCR) signaling, has emerged as a promising target of antitumor immunotherapy. Macrocyclization is an effective strategy to address the major challenges faced in the development of HPK1 inhibitors, as it can balance inhibitory efficacy, kinase selectivity, and pharmacokinetic properties. Herein, we continued this strategy and report a series of N-sulfonyl-pyrazole macrocyclic HPK1 inhibitors. Compound 14 exhibited excellent HPK1 inhibition with an IC (Copyright © 2024. Published by Elsevier Inc.) |
| Contributed Indexing: | Keywords: Hematopoietic progenitor kinase 1 inhibitor; N-sulfonyl-pyrazole; Synergistic effect |
| Substance Nomenclature: | 0 (Pyrazoles) 0 (Protein Kinase Inhibitors) 0 (Antineoplastic Agents) EC 2.7.1.11 (hematopoietic progenitor kinase 1) EC 2.7.11.1 (Protein Serine-Threonine Kinases) 0 (Macrocyclic Compounds) |
| Entry Date(s): | Date Created: 20251109 Date Completed: 20251203 Latest Revision: 20251203 |
| Update Code: | 20251204 |
| DOI: | 10.1016/j.bioorg.2025.109196 |
| PMID: | 41207223 |
| Database: | MEDLINE |
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Nájsť tento článok vo Web of Science | Abstract: | Hematopoietic progenitor kinase 1 (HPK1), due to its crucial intracellular negative regulation of T-cell receptor (TCR) signaling, has emerged as a promising target of antitumor immunotherapy. Macrocyclization is an effective strategy to address the major challenges faced in the development of HPK1 inhibitors, as it can balance inhibitory efficacy, kinase selectivity, and pharmacokinetic properties. Herein, we continued this strategy and report a series of N-sulfonyl-pyrazole macrocyclic HPK1 inhibitors. Compound 14 exhibited excellent HPK1 inhibition with an IC <subscript>50</subscript> value of 1.7 nM, as well as significant selectivity against GLK and LCK, which was confirmed in our molecular modeling studies to be caused by the interactions of cyclopropyl-sulfonyl group with different residues in the kinase domain. Compound 14 also displayed favorable human liver microsomal stability (T <subscript>1/2</subscript> = 147.3 min) and considerable oral bioavailability (F = 22.8 %) in mice. More importantly, compound 14 demonstrated an additive synergistic effect with anti-PD-1 in a MC38 syngeneic tumor mouse model with a TGI% value of 89 % which was exhibited more pronouncedly in further subgroup analysis. These results indicated that compound 14 provided a perspective vision when used in combination of anti-PD-1 antibody as a new treatment regimen for patients who have insufficient response to current immunotherapy.<br /> (Copyright © 2024. Published by Elsevier Inc.) |
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| ISSN: | 1090-2120 |
| DOI: | 10.1016/j.bioorg.2025.109196 |