Abstract LB-298: The novel triple PI3K-CDK4/6-BRD4 inhibitor SRX3177 harnesses synthetic lethality relationships to orthogonally disrupt cancer cell signaling

Abstract

Abstract Dysregulation of the cell cycle is a hallmark of nearly all cancers, and efforts to target signaling pathways regulating cell growth and proliferation have driven much of cancer drug discovery. Despite advances in novel therapeutics, however, most patients with advanced neoplasms do not achieve long-term survival with single agent targeted therapy. Here, we describe a novel “triple inhibitor” (i.e., SRX3177) that simultaneously targets three oncogenes promoting cancer cell growth: phosphatidylinositol-3 kinase (PI3K), cyclin-dependent kinases 4 and 6 (CDK4/6), and the epigenetic regulator BRD4. This rationally-designed, thieno-pyranone scaffold-based small molecule inhibitor uses known synthetic lethality relationships to orthogonally disrupt three targets within the cancer cell with one agent. Single agent CDK4/6 inhibitors such as palbociclib, which is FDA-approved in combination with hormone therapy in estrogen-receptor positive breast cancer, suffer from being cytostatic in nature, requiring combinations to be more effective and avoid development of resistance. Concurrent PI3K inhibition can prevent resistance to CDK4/6 inhibition, and combined CDK4/6 and PI3K inhibition leads to synthetic lethality reported in a number of cancer types, including breast cancer and mantle cell lymphoma. Moreover, blocking the chromatin reader protein BRD4 downregulates MYC and cyclin D1 transcription, further promoting cell cycle arrest in G1. Thus, we designed SRX3177 as a triple inhibitor of PI3K, CDK4/6, and BRD4 to maximally block cell cycle progression and cancer cell growth. SRX3177 is a potent ATP competitive CDK4/6 inhibitor (IC50: CDK4 = 2.54 nM, CDK6 = 3.26 nM), PI3K inhibitor (IC50: PI3Kα = 79.3 nM, PI3Kδ = 83.4 nM), and BRD4 inhibitor (IC50: BD1 = 32.9 nM, BD2 = 88.8 nM). In a panel of mantle cell lymphoma, neuroblastoma, and hepatocellular carcinoma cell lines, SRX3177 has maximal IC50 values of 578 nM, 385 nM, and 495 nM respectively. This represents a 19 to 82-fold increase in potency compared to palbociclib. SRX3177 is 5-fold more potent in cancer cells than the combination of similar potency single PI3K, CD4/6, and BRD4 inhibitors (i.e., BKM120 + palbociclib + JQ1). SRX3177 is also 40-fold less toxic to normal epithelial cells than the co-treatment with single inhibitors. Furthermore, SRX3177 induces cell cycle arrest and apoptosis in propidium iodide and annexin V assays, respectively. Finally, SRX3177 inhibits Akt and Rb phosphorylation (downstream of PI3K and CDK4/6 signaling, respectively) and blocks BRD4 binding to chromatin. Thus, our triple inhibitor SRX3177 is efficacious, is more potent and less toxic to normal cells than administration of three individual inhibitors, and has robust pharmacodynamic effects on its targets. Taken together, our data support the development of SRX3177 as a novel therapeutic agent for multiple cancers. Citation Format: Adam M. Burgoyne, Francisco M. Vega, Alok Singh, Shweta Joshi, Joseph R. Garlich, Guillermo A. Morales, Tatiana G. Kutateladze, Donald L. Durden. The novel triple PI3K-CDK4/6-BRD4 inhibitor SRX3177 harnesses synthetic lethality relationships to orthogonally disrupt cancer cell signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-298. doi:10.1158/1538-7445.AM2017-LB-298