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

08:00 EDT 14th July 2018 | BioPortfolio

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

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.


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This article was published in the following journal.

Name: Journal of controlled release : official journal of the Controlled Release Society
ISSN: 1873-4995


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Medical and Biotech [MESH] Definitions

Part of a MESSENGER RNA molecule that undergoes a conformation change upon binding a specific metabolite or other small molecule thereby regulating the messenger RNA's transcription, post-transcriptional processing, transport, translation, or stability in response to varying levels of the metabolite or other small molecule.

Genes, found in both prokaryotes and eukaryotes, which are transcribed to produce the RNA which is incorporated into RIBOSOMES. Prokaryotic rRNA genes are usually found in OPERONS dispersed throughout the GENOME, whereas eukaryotic rRNA genes are clustered, multicistronic transcriptional units.

Unstable isotopes of copper that decay or disintegrate emitting radiation. Cu atoms with atomic weights 58-62, 64, and 66-68 are radioactive copper isotopes.

P-type ATPases which transport copper ions across membranes in prokaryotic and eukaryotic cells. They possess a conserved CYSTEINE-HISTIDINE-SERINE (CPx) amino acid motif within their transmembrane helices that functions in cation translocation and catalytic activation, and an N-terminal copper-binding CxxC motif that regulates enzyme activity. They play essential roles in intracellular copper homeostasis through regulating the uptake, efflux and storage of copper ions, and in cuproprotein biosynthesis.

Within most types of eukaryotic CELL NUCLEUS, a distinct region, not delimited by a membrane, in which some species of rRNA (RNA, RIBOSOMAL) are synthesized and assembled into ribonucleoprotein subunits of ribosomes. In the nucleolus rRNA is transcribed from a nucleolar organizer, i.e., a group of tandemly repeated chromosomal genes which encode rRNA and which are transcribed by RNA polymerase I. (Singleton & Sainsbury, Dictionary of Microbiology & Molecular Biology, 2d ed)

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