Glioblastoma Multiforme (GBM) is an aggressive stage IV cancer that is difficult to detect, commonly inoperable, and associated with a poor prognosis. Challenges in targeting this disease are due to the various pro-survival signaling pathways, four different cellular states that encompass malignant GBM, and the individual heterogeneity of each tumor. Marketed FDA-approved drugs for GBM have shown improvement for this disease, but it is noted that these drugs have demonstrated low IC50 values, toxicity issues, and cancerous cells have displayed resistance to treatment. Further investigation into pathway breakdowns involved in GBM lead to the discovery of the Dual- specificity tyrosine phosphorylation- regulated kinases (DYRKS) upregulation in these pro-survival pathways. Research suggests that the inhibition of the DYRKs involved in GBM breakdown has caused degradation and deceleration of cancerous cell growth. Based on the results of DYR600, a pan-DYRK inhibitor for the treatment of GBM could be a promising direction for this disease type and supports these claims. DYR600 has been shown to display a high affinity and inhibition for the DYRK family [KD DYRK1A/B/2 (2.85/24/12 nM) and IC50 DYRK1A/B/2/3 (30/13/208/22 nM)], efficacy across various GBM cell lines [EC50 GL261/GBM184/22/6 (1-3/3/30/1-3 µM)], reduction in cell and neurosphere growth, and no observed toxicity to noncancerous cell lines. Additionally, DYR600 displays ideal pharmacokinetic properties with reasonable metabolic stability [MLM (T1/2 32.2 min) and HLM (T1/2 52.4 min)] and a predicted high blood-brain barrier (40.7 nm/s). Further evaluation, through a ScanMax, identified DYR600 as a selective kinase inhibitor [S(35)-selectivity (468 Kinases): 0.104 @ 1 µM] and identified additional targets that were inhibited by DYR600 that has presumably aided in its mechanism of action (MOA). Future directions for this project will be focused on exploring the structure-activity relationship (SAR) for this series, addressing solubility concerns (0.627 µg/mL) through bioisosteres and increasing fsp3, and evaluation of DYR600 in a xenograft mouse model study.

Evaluation of small molecule kinase inhibitors (SMKIs) as a multi-targeted therapeutic for the treatment of glioblastoma multiforme (GBM)?

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.