Abstract 437: Computational discovery and preclinical validation of therapeutic leads with novel MOAs for Glioblastoma

Abstract

Abstract Glioblastoma (GBM) is an aggressive, highly invasive tumor that has a 5-year survival rate of less than 5%, with median survival of approximately 15 months. Treatment options for patients with GBM are relatively unchanged over the past two decades. We present results from our early-stage GBM drug discovery program enabled by Symphony™, Aria Pharmaceutical’s artificial intelligence (AI) platform. Using patient-derived, unconnected multimodal data and a select chemical library of over 2 million characterized molecules as input, our AI platform built an interpretable in silico model of GBM disease biology and identified novel, high-value drug discovery hits with known pharmacological properties. Nine molecules with unique and novel MOAs (not clinically evaluated for GBM) were identified as drug discovery hits and evaluated in preclinical efficacy studies. Six out of the nine molecules showed anti-proliferative activity in 4 different GBM cell lines (U87MG, LN18, A172, and U118MG) (Table 1). The MOAs showing efficacy in this initial study were validated in a colony formation assay. Three target classes, stearoyl-CoA desaturase (SCD) inhibitor (MK8245 and MF-438), dual tyrosine-regulated kinase 3 (DYRK3) inhibitor (GSK626616), and heat shock protein 90 (HSP90) inhibitor (XL-888) potently inhibited colony formation in a 3D cell culture system. Pharmacokinetic studies showed that MF-438 had good metabolic stability and lower predicted clearance in human and mouse liver microsome assays. Further, MF-438 showed good exposure in plasma and brain extract (brain-to-plasma ratio of 2.2). SCD is a lipogenic enzyme that plays a key role in tumor lipid metabolism and membrane architecture and is often up-regulated in cancer. These studies demonstrate that the SCD1 inhibitor MF-438 can serve as a valuable tool compound that warrants further investigation as a potential treatment for GBM. Table 1. Molecules assessed in GBM cell lines Molecule Mechanism of Action (MOA) Proliferation Assay 3D Colony Formation Assay AS-605240 Phosphoinositide-3 kinase (PI3K), Dual specificity tyrosine-phosphorylation-regulated kinase (DYRK), and CDC like kinase (CLK1) inhibitor Positive Not tested (GSK626616 selected to investigate DYRK inhibition) GSK626616 Dual specificity tyrosine-phosphorylation-regulated kinase (DYRK) 3 inhibitor Not tested Positive Anilinopyrimidine1 Aurora A kinase (AURKA) and Lymphocyte-specific protein tyrosine kinase (LCK) inhibitor Positive Negative Entospletinib Spleen tyrosine kinase (SYK) inhibitor Negative Not tested T0901317 Liver X receptor (LXR) inhibitor Positive Negative MK-8245 Stearoyl-CoA desaturase (SCD) inhibitor Positive Positive MK-438 Stearoyl-CoA desaturase (SCD) inhibitor Not tested Positive Nedocromil Cysteinyl leukotriene receptor 1 (CYSLTR1) and 2 (CYSLTR2) inhibitor Negative Not tested DB07268 c-Jun N-terminal kinase (JNK1) inhibitor Positive Negative PF-670462 Casein kinase 1-e (CSNK1E) and 1-d (CSNK1D) inhibitor Negative Not tested XL888 Heat shock protein 90 (HSP90) inhibitor Positive Positive Citation Format: Hyekyoung Kim, Aaron C. Daugherty, Sana Mujahid, Isaac I. Hakim, Anjali Pandey, Inyong Bae, Jinhwa Lee. Computational discovery and preclinical validation of therapeutic leads with novel MOAs for Glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 437.