Zelenirstat

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Zelenirstat

CAS 1215011-08-7

MF C24H30Cl2N6O2S, 537.5 g/mol

2,6-dichloro-N-[1,5-dimethyl-3-(2-methylpropyl)-1Hpyrazol-4-yl]-4-[2-(piperazin-1-yl)pyridin-4-yl]benzene-1-sulfonamide
N-myristoyltransferase inhibitor, antineoplastic, PCLX 001, DDD86481, CCI 002, DDD 86481

Zelenirstat (PCLX-001) is an investigational, oral small-molecule drug that inhibits N-myristoyltransferases (NMTs), enzymes crucial for adding fatty acids to proteins, a process vital for cell signaling and membrane attachment. Developed by Pacylex Pharmaceuticals, it’s being tested for various cancers, showing promise in hematologic cancers like AML and lymphomas, as well as solid tumors, by disrupting cancer cell survival and growth, with early trials indicating good safety and potential efficacy. 

How it works:

  • Targets NMT enzymes: Zelenirstat blocks NMT1 and NMT2, preventing myristoylation (adding a fatty acid) to proteins.
  • Disrupts cancer cell processes: This inhibition interferes with essential cell signaling and stability, especially in cancer cells where NMT expression is altered, leading to cell death (apoptosis).
  • Affects mitochondrial function: It also disrupts mitochondrial complex I and oxidative phosphorylation, vital for leukemia stem cell survival, notes Pacylex Pharmaceuticals. 

Development & Status:

  • Orphan Drug Status: Granted for Acute Myeloid Leukemia (AML).
  • Clinical Trials: A Phase 1 trial demonstrated good safety and early signs of activity in patients with advanced solid tumors and lymphomas, leading to further development.
  • New Drug Class: It represents a novel approach to cancer treatment, distinct from many existing therapies. 

Potential Applications:

  • Acute Myeloid Leukemia (AML)
  • B-cell Lymphomas (like Diffuse Large B-Cell Lymphoma)
  • Colorectal Carcinoma
  • Other cancers, including breast, lung, bladder, and pancreatic cancers, show sensitivity in preclinical models. 

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]

Zelenirstat is an orally bioavailable inhibitor of the enzyme N-myristoyl transferase (NMT), with potential antineoplastic activity. Upon oral administration, zelenirstat targets and binds to NMT, especially NMT type 2 (NMT2). This prevents NMT-mediated signaling and myristoylation. This inhibits proliferation of certain cancer cells in which NMT expression is lost. Zelenirstat also inhibits B-cell receptor (BCR) signaling and reduces the levels of Src-family tyrosine kinases (SFKs). NMTs mediate myristoylation, a key process by which the fatty acid myristate is added to proteins and allows proteins to interact with cell membranes and become part of the cell signaling system. NMT expression is lost in numerous cancers, such as blood cancer cells, thereby making these cells more sensitive to zelenirstat compared to normal cells. The loss of NMT expression may promote tumorigenesis.

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]

PCLX-001 is a first-in-kind N-Myristoyltransferase (NMT) inhibitor being developed by [Pacylex Pharmaceuticals](https://pacylex.com). Current studies have shown that PCLX-001 works differently than other known cancer drugs and has high activity and positive results in breast, lung, bladder and pancreas cancers.

  • Study of PCLX-001 in R/R Advanced Solid Malignancies and B-cell LymphomaCTID: NCT04836195Phase: Phase 1Status: CompletedDate: 2025-04-17
  • Study of Oral PCLX-001 in R/R Acute Myeloid LeukemiaCTID: NCT06613217Phase: Phase 1Status: RecruitingDate: 2025-03-10

REF

SYN

US9156811B2

DDD 86481

https://patentscope.wipo.int/search/en/detail.jsf?docId=US73438944&_cid=P12-MJAUPA-00022-1

INTERMEDIATE 23A

4-Bromo-2,6-dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

      Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (0.68 g, 2.1 mmol) and 4-amino-1,5-dimethyl-3-isobutyl-1H-pyrazole (0.35 g, 2.1 mmol) in pyridine (5 ml) according to the method of intermediate 1, to give the title compound as a white solid (120 mg, 0.26 mmol, 12%). δH (D-6 DMSO, 300K) 7.65 (2H, s), 6.54 (1H, s), 3.70 (3H, s), 2.17 (3H, s), 1.96 (2H, d J 7.9 Hz), 1.74 (1H, m), 0.78 (6H, d J 6.6 Hz). m/z (ES +, 70V) 456.0 (MH +).

EXAMPLE DDD86481

2,6-Dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

      Prepared from the sulphonamide of intermediate 23A (115 mg, 0.25 mmol), 2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28 mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh 3) 4 (30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.4 ml), according to the method of intermediate 11, to give the title compound as a yellow solid (73 mg, 0.14 mmol, 54%). δH (D-6 DMSO, 300K) 8.20, (1H, d J 5.2 Hz), 8.06 (2H, s), 7.15 (1H, s), 7.02 (1H, d J 5.2 Hz), 3.60 (3H, s), 3.52 (4H, m), 2.80 (4H, m), 1.98 (3H, s), 1.92 (2H, d J 7.3 Hz), 1.70 (1H, m), 0.70 (6H, d J 6.6 Hz). m/z (ES +, 70V) 537.2 (MH +).

SYN

WO-2010026365

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010026365&_cid=P12-MJAUOO-99381-1

PAT

N-myristoyl transferase inhibitors

Publication Number: WO-2010026365-A1

Priority Date: 2008-09-02

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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.
Clinical data
Other namesPCLX-001
Identifiers
IUPAC name
CAS Number1215011-08-7
PubChem CID58561243
DrugBankDB15567
ChemSpider35034199
UNII5HY8BYC3Q6
ChEMBLChEMBL3357685
Chemical and physical data
FormulaC24H30Cl2N6O2S
Molar mass537.50 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

////////zelenirstat, N-myristoyltransferase inhibitor, antineoplastic, PCLX 001, DDD86481, CCI 002, DDD 86481

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