Zelenirstat

Last updated

Zelenirstat
Zelenirstat.svg
Clinical data
Other namesPCLX-001
Identifiers
  • 2,6-Dichloro-N-[1,5-dimethyl-3-(2-methylpropyl)pyrazol-4-yl]-4-(2-piperazin-1-ylpyridin-4-yl)benzenesulfonamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C24H30Cl2N6O2S
Molar mass 537.50 g·mol−1
3D model (JSmol)
  • CC1=C(C(=NN1C)CC(C)C)NS(=O)(=O)C2=C(C=C(C=C2Cl)C3=CC(=NC=C3)N4CCNCC4)Cl
  • InChI=1S/C24H30Cl2N6O2S/c1-15(2)11-21-23(16(3)31(4)29-21)30-35(33,34)24-19(25)12-18(13-20(24)26)17-5-6-28-22(14-17)32-9-7-27-8-10-32/h5-6,12-15,27,30H,7-11H2,1-4H3
  • Key:WKTSLVQYGBHNRV-UHFFFAOYSA-N

Zelenirstat, also known as PCLX-001, is an investigational new drug that is being evaluated for the treatment of cancer and as an antiviral agent. It is a small molecule inhibitor targets both N-myristoyltransferase 1 (NMT1) and N-myristoyltransferase 2 (NMT2) proteins, which are responsible for myristoylation. Its dual mechanism of action disrupts both cell signaling and energy production in cancer cells.

Zelenirstat is a strong pan-N myristoyl transferase inhibitor, which prevents addition of myristic acid into penultimate glycine of protein with myristoylation signal, and initially has been introduced as anti-tumor drug. [1] [2] [3] It has completed phase I clinical trial and is going through escalation phase. [4] Its prototype DDD85646 as well as other NMT inhibitors such as IMP-1088 have strong antiviral activities against viruses that required myristoylated proteins to complete their life cycle, including hemorrhagic viruses, such as lassa and argentinian virus, and pox viruses, such as vaccinia and monkeypox. [5] [6]

Mechanism of action

Zelenirstat acts by inhibiting NMT I and II enzymes, which are required to complete the myristoylation of proteins. Without myristoylation, these proteins are targeted for proteasomal degradation. [7]

References

  1. ↑ Gamma JM, Liu Q, Beauchamp E, Iyer A, Yap MC, Zak Z, et al. (January 2025). "Zelenirstat Inhibits N-Myristoyltransferases to Disrupt Src Family Kinase Signaling and Oxidative Phosphorylation, Killing Acute Myeloid Leukemia Cells". Molecular Cancer Therapeutics. 24 (1): 69–80. doi:10.1158/1535-7163.MCT-24-0307. PMC   11694064 . PMID   39382188.
  2. ↑ Sangha R, Jamal R, Spratlin J, Kuruvilla J, Sehn LH, Beauchamp E, et al. (August 2024). "A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas". Investigational New Drugs. 42 (4): 386–393. doi:10.1007/s10637-024-01448-w. PMC   11327210 . PMID   38837078.
  3. ↑ Sangha RS, Jamal R, Spratlin J, Kuruvilla J, Sehn LH, Weickert M, et al. (June 2024). "Final results of a first-in-human phase I dose escalation trial of daily oral zelenirstat, a n-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas". Journal of Clinical Oncology. 42 (16_suppl): 3082. doi:10.1200/JCO.2024.42.16_suppl.3082. ISSN   0732-183X.
  4. ↑ Spratlin JL, Sangha RS, Jamal R, Beauchamp E, Berthiaume LG, Mackey JR (20 January 2024). "A first-in-human, open-label, phase I trial of daily oral zelenirstat, an NMT inhibitor, in patients with relapsed/refractory advanced cancer including gastrointestinal cancers" . Journal of Clinical Oncology. 42 (3_suppl): 129–129. doi:10.1200/jco.2024.42.3_suppl.129 . Retrieved 19 January 2025.
  5. ↑ Witwit H, Betancourt CA, Cubitt B, Khafaji R, Kowalski H, Jackson N, et al. (August 2024). "Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication". Viruses. 16 (9): 1362. doi: 10.3390/v16091362 . PMC   11436053 . PMID   39339839.
  6. ↑ Witwit H, Cubitt B, Khafaji R, Castro EM, Goicoechea M, Lorenzo MM, et al. (January 2025). "Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance". Viruses. 17 (1): 92. doi: 10.3390/v17010092 . ISSN   1999-4915. PMC   11769280 .
  7. ↑ Witwit H, Betancourt CA, Cubitt B, Khafaji R, Kowalski H, Jackson N, et al. (August 2024). "Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication". Viruses. 16 (9): 1362. doi: 10.3390/v16091362 . PMC   11436053 . PMID   39339839.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.