Samantha Rokey Wins 1st Place at Arizona Drug Discovery Summit

Samantha Rokey, a graduate student in the Hulme Lab, represented the Chemistry and Biochemistry Department at the 5th Annual Arizona Drug Discovery and Development Summit this past week. Samantha gave a 10-minute oral presentation, “DYR895: An orally bioavailable, brain penetrant, SMKI toward glioblastoma and colorectal cancer”, as part of the Student Presentation Series where she placed 1st. 

Abstract:
Glioblastoma (GBM) is a highly invasive and refractory brain neoplasia with a median patient survival of 12-15 months from initial diagnosis. The high plasticity and proliferative nature of GBM poses a major challenge for mono-therapeutic drugs that target the disease. Multiple brain-penetrant drugs targeting PI3K, PDGFR, EGFR, mTOR, and others have been tried and tested with suboptimal outcomes driven by the highly heterogenous glioma stem cell population. The stemness-driven plasticity has been attributed to two main cancer stemness pathways - WNT-β-catenin and PI3K-AKT-MTOR. A successful therapeutic strategy may thus require multi-targeted interventions for diverse survival pathways of the disease. WNT-β-catenin signaling is also a major driver of colorectal cancer (CRC), the third most common cancer worldwide. Indeed, 90% of CRC patients display somatic mutations within the pathway and aberrant activation leads to initiation and progression of nearly all CRCs.

Beginning with DYR533 (a selective DYRK1A inhibitor soon to commence IND enabling studies – Alzheimer’s disease), we tempered selectivity to induce pan-DYRK/CLK activity. The latter kinases have been shown to inhibit WNT signaling through their effects on mRNA splicing. Fortuitously new congeners also picked up significant activity versus CDK7, CDK8, and CDK19 additional drivers of WNT signaling affording benchmarked molecules that appear to be one of the strongest WNT inhibitors reported. One such molecule DYR726 also possessed single digit nM affinity for PDGFRA (+ mutants) and PI3Kα (-selective + mutants) and thus uniquely inhibits both major cancer stemness pathways, supported by target engagement studies (i.e. ablation of p-AKT & p-ERK & p-S6K levels). Iterative property-based design with maintenance of this exquisite multi-targeted profile subsequently led to the discovery of DYR895 (WNT EC50 5 nM) with nominal cytotoxicity in non-cancerous cell lines (HCEC GI50 6.5 µM) and excellent activity in three primary GBM cell lines (GBM6 EC50 0.61 µM; GBM 22 1.93 µM; GBM143 2.15 µM) and a diverse set of CRC cell lines (EC50: 9.3 nM-520 nM). DYR895 is orally bioavailable (F% 82% mouse, T1/2 3 h), well-tolerated (MTD > 50mg/kg) and brain penetrant (Kpuu 1.59, BCRP & MDR1 < 3.0) with limited efflux. Despite its multi-targeted nature, DYR895 remains a relatively selective molecule within the kinome [S(35)-score 0.14] superior to both Cirtuvivint (Biosplice, Phase 1 CRC) and Abemaciclib (Lilly, breast cancer approved, glioma trails on-going). DYR895 has high physiologically relevant unbound drug concentrations in brain and plasma which will enable dosing >>> 10-fold key IC50s @25 mg/kg. As such, in vivo studies have finished in GBM PDX models and orthostatic models of CRC. DYR895 is also clean in a Eurofins Safety Pharmacology panel (78) and is undergoing other mechanism-based safety studies. Intellectual property is secure.