Zabadinostat

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Zabadinostat
Names
Preferred IUPAC name
N-(2-aminophenyl)-4-[1-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-piperidinyl]-benzamide
Other names
CXD101, AZD-9468
Identifiers
3D model (
JSmol
)
ChEMBL
ChemSpider
DrugBank
UNII
  • InChI=1S/C24H29N5O/c1-17-21(15-28(2)27-17)16-29-13-11-19(12-14-29)18-7-9-20(10-8-18)24(30)26-23-6-4-3-5-22(23)25/h3-10,15,19H,11-14,16,25H2,1-2H3,(H,26,30)
    Key: JHDZMASHNBKTPS-UHFFFAOYSA-N
  • CC1=NN(C=C1CN2CCC(CC2)C3=CC=C(C=C3)C(=O)NC4=CC=CC=C4N)C
Properties
C24H29N5O
Molar mass 403.530 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Zabadinostat is an experimental

epigenetic drug
being investigated as a potential treatment for advanced or metastatic cancers. It is an orally available Class I selective
half maximal inhibitory concentrations (IC50) of 62 nM, 570 nM and 550 nM, against HDAC1, HDAC2 and HDAC3, respectively. It shows no activity against HDAC class II.[1]

Chemistry

The ortho-aminoanilide or

acetyl group from lysine
residues, preventing substrate deacetylation. As such, zabadinostat is chemically distinct from earlier generations of less selective pan-HDAC inhibitors, such as vorinostat, belinostat and panobinostat, which bind Zn2+ ions through their hydroxamic acid groups.[2]

Research

Experiments in human and murine

natural killer (NK) cell-mediated cytotoxicity.[3]

Further experiments showed that zabadinostat treatment in mice altered their

CTLA4.[4]

In addition, mice immunized with the

neutralising antibodies and an increased level of CD4+ and CD8+ T lymphocytes, suggesting potential uses beyond cancer.[5]

Clinical studies

Zabadinostat is being investigated as a treatment for late-stage cancers, including relapsed or refractory lymphoma, microsatellite stable colorectal cancer, and hepatocellular carcinoma, the most common form of liver cancer.[6]

Lymphoma

A

Phase I clinical trial (NCT01977638) conducted in late-stage cancer patients unresponsive to conventional therapy found that zabadinostat treatment resulted in anti-cancer responses for follicular lymphoma (FL), classic Hodgkin lymphoma (HL), and peripheral T-cell lymphoma
(PTCL). The most common Grade 3 and above treatment-related adverse events (TRAE) were neutropenia (17%), thrombocytopenia (11%) and leukopenia (5%). Serious adverse events (SAE) were infrequent, and included
bronchial infection
(<1%). No treatment-related deaths occurred on study. The recommended Phase 2 dose (RP2D) was found to be 20 mg twice daily (
b.i.d.).[7]

Colorectal cancer

A single-arm

Phase II clinical trial (NCT03993626) combining zabadinostat and nivolumab showed that it was effective in treating metastatic microsatellite-stable (MSS) colorectal cancer patients who had progressed despite receiving at least two lines
of systemic anti-cancer therapies. The combination therapy was well tolerated with the most frequent Grade 3 or 4 adverse events being neutropenia (18%) and anemia (7%). Immune-related adverse reactions commonly ascribed to checkpoint inhibitors were surprisingly rare although single cases of pneumonitis, hypothyroidism and hypopituitarism were seen. There were also no treatment-related deaths. Of 46 patients assessable for efficacy, 4 (9%) achieved partial response and 18 (39%) achieved stable disease, translating to an immune disease control rate of 48%. The median
overall survival (OS) was 7.0 months with a 95% confidence interval
of 5.13–10.22 months. The study met its
primary endpoint demonstrating anti-tumour efficacy in 3rd line and above MSS colorectal cancer.[8]

Liver cancer

In 2023, a

Phase II clinical trial (NCT05873244) will be conducted in hepatocellular carcinoma (HCC) patients that demonstrate resistance to immune-checkpoint inhibitor
(ICI) treatment. Study patients will be randomly assigned in a 1:1 ratio to either zabadinostat plus geptanolimab (experimental arm), or the best available standard treatment, lenvatinib or sorafenib (control arm). The
primary endpoint will be progression-free survival (PFS).[9]

History

Zabadinostat was originally a chemical compound (codenamed AZD-9468) synthesized by AstraZeneca. Later, AstraZeneca entered into a License Agreement with Celleron Therapeutics, granting it exclusive worldwide rights to develop and commercialize AZD-9468.[10] During its Phase I and early Phase II development, the compound was known as CXD101,[11] until in 2022, when the World Health Organization (WHO) included the name zabadinostat in its official list of International Nonproprietary Names (INN) for Pharmaceutical Substances.[12] Zabadinostat is now an asset of IngenOx Therapeutics, following its formation in January 2023 from the merger of Celleron Therapeutics and Argonaut Therapeutics.[13]

References

  1. PMID 30647865
    .
  2. S2CID 226416184
    .
  3. PMID 33773029
    .
  4. PMID 33773029
    .
  5. PMID 36702861
    .
  6. ^ "Pipeline". 6 January 2023.
  7. S2CID 52986392
    .
  8. PMID 36327756
    .
  9. ^ "CXD101 in Immunotherapy-related Liver Cancer". ClinicalTrials.gov. Retrieved 22 December 2023.
  10. ^ "Celleron secures rights to AstraZeneca cancer candidate". 28 May 2009.
  11. ^ "CTG Labs - NCBI".
  12. ^ https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/pl127.pdf?sfvrsn=8544ca1e_3&download=true
  13. ^ "Celleron Therapeutics and Argonaut Therapeutics Announce Completion of Merger to Form IngenOx Therapeutics". 5 January 2023.
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