Pixantrone dimaleate

Pixantrone maleate (CAS No. 6108-05-0) is a topoisomerase II (IIα/IIβ) inhibitor, and also a multitarget inhibitor of cervical cancer-related targets DNA polymerase ε subunit, integrin α-V β-8, and TBK1; it is involved in regulating topoisomerase II-mediated maintenance of DNA topology, DNA replication and repair pathways, arenavirus (Lassa virus LASV, Junín virus JUNV, lymphocytic choriomeningitis virus LCMV) genome replication and translation pathways, and the type I interferon signaling pathway (which can stimulate interferon production to counteract immune evasion by arenaviral nucleoproteins).

In in vitro cell-based assays, the IC50 for inhibiting LASV minigenome activity was 1.01 μM, the IC50 for inhibiting JUNV minigenome activity was 1.81 μM, the IC50 for inhibiting live JUNV replication was 3.66 μM, and the IC50 for inhibiting recombinant LCMV infection was 4.75 μM. Molecular docking showed docking scores with DNA polymerase ε, integrin α-V β-8, and TBK1 of - 8.147, -8.206, and -7.310 kcal/mol, respectively, and MM/GBSA binding energies of - 40.55, -33.67, and -37.64 kcal/mol, respectively; 5 μM is commonly used for initial screening in cell assays, followed by IC50 determination using a concentration gradient.

Clinically, it is an FDA-approved marketed drug for the treatment of relapsed or refractory peripheral T-cell lymphoma. Pharmacokinetic data show a molecular weight of 325.369 g/mol, human oral absorption of 26.004%, low blood-brain barrier permeability, compliance with Lipinski's rule of five, and a selectivity index against LASV of 9.21.

References:

[1] Almasoudi HH, Nahari MH, Alhazmi AYM, Almasabi SHA, Al-Mansour FSH, Hakami MA. Delineating Pixantrone Maleate's adroit activity against cervical cancer proteins through multitargeted docking-based MM\GBSA, QM-DFT and MD simulation. PLoS One. 2023 Dec 15;18(12):e0295714. doi: 10.1371/journal.pone.0295714. PMID: 38100507; PMCID: PMC10723688.

[2] Afowowe TO, Sakurai Y, Urata S, Zadeh VR, Yasuda J. Topoisomerase II as a Novel Antiviral Target against Panarenaviral Diseases. Viruses. 2022 Dec 30;15(1):105. doi: 10.3390/v15010105. PMID: 36680145; PMCID: PMC9866940.