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 poor 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) and CDC2-like kinases (CLKs) upregulation in these pro-survival pathways. Evidence suggests that the inhibition of the DYRKs and CLKs involved in various signaling pathways can affect the proliferation, spread, invasiveness, and malignancy commonly associated with GBM. Based on the results from our initial hit DYR600, a pan-DYRK/CLK inhibitor for the treatment of GBM could be a promising direction for this disease type and supports the biological rational. Through multi-parameter optimizations (MPOs), this led to the discovery of our current lead compound, DYR726, a highly soluble with a high predicted permeability that has demonstrated significant kinase inhibition against GBM, while inducing reduction in growth, proliferation, invasion, and malignancy across various patient derived GBM cell lines. Investigation to optimize and improve metabolic liabilities associated wtih DYR726 have been underway and led to the discovery of DYR701 and DYR785.

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

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