The Discovery of Small Molecule Kinase Inhibitors (SMKIs) for the Treatment of Solid Tumors

Abstract

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 can display resistance to treatment. Further investigation into pathway breakdowns involved in GBM led 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 is involved in various signaling pathways that affect the proliferation, spread, invasiveness, and malignancy commonly associated with GBM. Based on our initial hit DYR600 results, the series was discovered to have a unique MOA and display affinity for the PI3Ks and PDGFRs. Through a pKa-driven approach, DYR726 was discovered, 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. Optimization to improve the known metabolic liabilities of DYR726, lead to the discovery of DYR895 an orally bioavailable, safe, and +CNS penetrant molecule. The POC DYR726 and lead DYR895 are currently being evaluated in-vivo for glioma, but their unique polypharmacology allows them also to be evaluated for other solid tumors like CRC and TNBC.