EXTH-52. SYSTEMIC AND BRAIN PHARMACOKINETICS OF THE AMP-ACTIVATED PROTEIN KINASE SELECTIVE INHIBITOR SBI-0206965 AS A POTENTIAL THERAPEUTIC AGENT FOR THE TREATMENT OF GLIOBLASTOMA MULTIFORME. (12th November 2021)

• Record Type: Journal Article
• Authors: Desai, Janki; Gawali, Mruniya; Karve, Aniruddha; Gudelsky, Gary; Sallans, Larry; Dasgupta, Biplab; Seibel, William; Desai, Pankaj
• Is Part Of: Neuro-oncology. Volume 23: Supplement 6(2021)
• Page Start: vi175
• Page End: vi175
• Publication Date: 2021-11-12
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab196.691
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: PURPOSE: AMP-activated protein kinase (AMPK) is a molecular hub for cellular metabolic control. Recent evidence suggests that AMPK is a "druggable" novel target for the treatment of Glioblastoma Multiforme (GBM). However, AMPK-inhibitory compounds are largely limited to compound C, which has a poor selectivity profile. SBI-0206965 is a diaminopyrimidine derivative that directly inhibits AMPK with 40-fold greater potency and markedly lower kinase promiscuity than compound C. The current studies provide insights into systemic pharmacokinetics and plasma to brain partitioning of SBI-0206965. METHODS: We conducted an intracerebral microdialysis study employing jugular vein-cannulated Sprague Dawley rats (males, 6- 8 weeks). Serial brain extracellular fluid (ECF) and venous blood samples were collected up to 10 hrs following intraperitoneal administration of SBI-0206965 (25 mg/kg). These samples were then quantitated for SBI-0206965 levels using a LC/MS method (Thermo Scientific LTQ-FT™, Ionization: Electrospray Ionization; positive ion). PK analysis was performed using the Non–Compartmental Analysis (Phoenix® WinNonlin 8.2 Certara USA, Inc.). RESULTS: Plasma and ECF peak concentrations (Cmax ) were 7.15 µM and 0.68 µM, whereas the time to peak (Tmax ) were 0.5 and 1 hr, respectively. The plasma and brain ECF elimination half-lives were 1.5 and 3 hours, respectively. Plasma protein binding of SBI-0206965 was 82%. A comparison of the brain ECF Cmax and area under the curve (AUC) to corresponding plasma values suggested that the brain partitioning of the compound was 10-18%. When corrected for unbound fraction in plasma the AUC ratio was 0.86. Thus, these studies show that SBI-0206965 has adequate brain penetration. Further studies are now in progress to assess selectivity of SBI-0206965 for AMPK expressing cell lines, efficacy against patient-derived GBM and PK in tumor-bearing mice. CONCLUSION: Results from this study will help to design optimal dosing regimen of SBI-0206965 in our efforts to explore AMPK as a GBM-specific drug target.