Copper-CX-5461: A novel liposomal formulation for a small molecule rRNA synthesis inhibitor

J Control Release. 2018 Sep 28;286:1-9. doi: 10.1016/j.jconrel.2018.07.025. Epub 2018 Jul 18.

Abstract

CX-5461 is currently in Phase I/II clinical trials for advanced hematologic malignancies and triple negative or BRCA-deficient breast cancer. The compound is currently administered to patients intravenously (i.v.) at low pH (3.5) due to solubility challenges. Reliance of low pH to enhance solubility of CX-5461 can adversely impact pharmacokinetics, biodistribution and therapeutic potential. We have addressed this solubility issue through a formulation method that relies on the interactions between CX-5461 and copper. Copper binds CX-5461 through the nitrogens of the pyrazine ring. Here, we describe synthesizing this copper-complexed CX-5461 (Cu(CX-5461)) within liposomes. CX-5461 was added to copper-containing liposomes and incubated at 60 °C for 30 min. The pharmacokinetics of CX-5461 was assessed in mice following a single i.v. injection at 30 mg/kg. Efficacy studies were completed in multiple subcutaneous mouse xenografts as well as in a bone marrow engraftment model of acute myeloid leukemia (AML). The novel Cu(CX-5461) formulation was stable at pH 7.4 and exhibited increased plasma circulation longevity, increasing the total exposure to CX5461 by an order of magnitude. Cu(CX-5461) was more active than CX-5461 in AML models in vivo. In HCT116-B46 and Capan-1 solid tumour models that are BRCA-deficient, the Cu(CX-5461) formulation engendered activity that was comparable to that of the low pH CX-5461 formulation. We have generated the first Cu(CX-5461) formulation suitable for i.v. administration that is more efficacious than the existing low-pH formulation in pre-clinical models of AML. The Cu(CX-5461) formulation may serve as an alternative formulation for CX-5461 in BRCA-deficient cancers.

Keywords: BRCA-deficient cancers; CX-5461; Leukemia; Liposomes; RNA polymerase I; Ribosomal biogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Benzothiazoles / administration & dosage*
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacokinetics
  • Benzothiazoles / therapeutic use
  • Cell Line, Tumor
  • Coordination Complexes / administration & dosage
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacokinetics
  • Coordination Complexes / therapeutic use
  • Copper / administration & dosage*
  • Copper / chemistry
  • Copper / pharmacokinetics
  • Copper / therapeutic use
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Liposomes / chemistry
  • Mice
  • Naphthyridines / administration & dosage*
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacokinetics
  • Naphthyridines / therapeutic use
  • RNA, Ribosomal / antagonists & inhibitors
  • RNA, Ribosomal / metabolism
  • Tissue Distribution

Substances

  • Antineoplastic Agents
  • Benzothiazoles
  • CX 5461
  • Coordination Complexes
  • Liposomes
  • Naphthyridines
  • RNA, Ribosomal
  • Copper

Grant support