Wild-type FVB mice received either vehicle control or 5 mg/kg of inhibitor, {either elacridar or “type”:”entrez-nucleotide”,LY335979 (zosuquidar) by tail vein injection

Wild-type FVB mice received either vehicle control or 5 mg/kg of inhibitor, {either elacridar or “type”:”entrez-nucleotide”,LY335979 (zosuquidar) by tail vein injection. distribution of SAR405838 to the brain. Concomitant administration of elacridar significantly increased brain exposure, also without affecting the systemic exposure. This study characterized the brain distributional kinetics of SAR405838, a novel MDM2 inhibitor, to evaluate its potential in the treatment of primary and metastatic brain AG-120 (Ivosidenib) tumors. SIGNIFICANCE STATEMENT This paper examined the brain distributional kinetics of a novel MDM2-p53 targeted agent, SAR405838, to see its possible application for brain tumors by using in vitro, in vivo, and in silico approaches. SAR405838 is found to be a substrate of P-glycoprotein (P-gp), which limits its distribution to the brain. Based on the findings in the paper, manipulation of the function of P-gp can significantly increase the brain exposure of SAR405838, which may give an insight on its potential benefit as a treatment for primary and metastatic brain cancer. Introduction The tumor suppressor p53 has been an attractive target in cancer therapeutics due to its crucial role in tumorigenesis (Hainaut and Hollstein, 2000; Vogelstein et al., 2000). The signaling pathway of p53 is found to be inactivated in various types of human cancers, often without a gene mutation in p53 itself (Wade et al., 2013). Therefore, it was a challenge to find ways to reactivate this protein in tumor cells for therapeutic purposes, until the role of the oncoprotein murine double minute 2 (MDM2) was discovered (Momand et al., 1992; Finlay, 1993). MDM2 has been identified as a major negative regulator of p53 by either direct binding or ubiquitination, leading to degradation (Momand et al., 2000; Wade et al., 2013). MDM2 is often amplified or overexpressed in various tumors, which leads to cancer development by downregulating p53 (Wade et al., 2013). Therefore, reactivation of p53 in tumors by AG-120 (Ivosidenib) the use of small molecule antagonists that target the interaction between MDM2 and p53 has been investigated as a novel molecularly targeted therapy for various cancers. Currently there are several small molecule MDM2 antagonists under clinical investigation for various solid tumors. One of Rabbit Polyclonal to DNA-PK these, SAR405838 (Fig. 1), is a potent inhibitor that has high selectivity and affinity to MDM2 (= 4 at each time point). Mouse whole blood was collected via cardiac puncture using heparinized syringes after mice were euthanized in a carbon dioxide chamber. Plasma was separated by centrifuge at 3500 rpm at 4C for 20 minutes. Plasma AG-120 (Ivosidenib) and brain samples were stored at ?80C until LC-MS/MS analysis. Pharmacological Inhibition of Efflux Transporters Elacridar (a dual inhibitor of P-glycoprotein and Bcrp) and “type”:”entrez-nucleotide”,”attrs”:”text”:”LY335979″,”term_id”:”1257451115″,”term_text”:”LY335979″LY335979 (zosuquidar, a selective P-gp AG-120 (Ivosidenib) inhibitor) were prepared in a microemulsion formulation as described previously (Sane et al., 2013). Both inhibitors formulated in the microemulsion were diluted with two volumes of sterile water to a final concentration of 1 mg/ml. Vehicle control was formulated in the same manner, including all components of the microemulsion, but without any inhibitor. Wild-type FVB mice received either vehicle control or 5 mg/kg of inhibitor, either elacridar or “type”:”entrez-nucleotide”,”attrs”:”text”:”LY335979″,”term_id”:”1257451115″,”term_text”:”LY335979″LY335979 (zosuquidar) by tail vein injection. A dose of 25 mg/kg of SAR405838 was administered orally 1 hour after the administration of either vehicle control or inhibitors. Blood and brain samples were collected as described in pharmacokinetic experiment, 2 hours following the administration of SAR405838,.