ABSTRACT:The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases.

IDO1/TDO* mediate substantial immunosuppressive effects through the metabolism of tryptophan (Trp) to kynurenine (Kyn). The consequent decrease in Trp suppresses T cell activity by multiple mechanisms, including the activation of GCN2 and mTOR pathways. Additionally, increased levels of Kyn further enhance the effect of Trp metabolism by engagement of aryl hydrocarbon receptor and potentially enhancing the number and activity of regulatory T cells. Taken together, expression of IDO1 and TDO in the tumor micro-environment dampens tumor-specific effector T cell response, and elevated expression of IDO1/TDO correlates with reduced survival of cancer patients. IDO1 selective inhibitors have already demonstrated clinical anti-tumor activity for certain tumor types. Therefore, targeting the Trp/Kyn pathway via simultaneous inhibition of IDO1 and TDO enzymes has the potential to bring enhanced benefit to cancer patients by relieving immunosuppression in a wide variety of tumor types. We have discovered a novel, highly potent, small molecule IDO1/TDO dual inhibitor, RG70099, with favorable preclinical oral bioavailability and safety profile. RG70099 potently inhibits both enzymes in cell based assays (IDO1 IC50: <100nM while TDO IC50: <100nM) and in preclinical in vivo model systems, a single oral administration of RG70099 efficiently prevented the formation of Kyn by ∼90% at plasma level. Furthermore, RG70099 efficiently penetrates into IDO1+ tumors and tumor draining lymph nodes where it reduced Kyn levels by more than 95%. We evaluated the inhibitory activity of the molecule in the TDO+ U87MG mouse tumor model. Twice-a-day administration of RG70099 reduced Kyn concentration in TDO+ tumors by ∼90% while pure IDO1 inhibitors failed to modulate Kyn levels in this setting. Studies of IDO1/TDO dual inhibition in pre-clinical immunocompetent animal models, and whether TDO inhibition in tumors that express IDO1 and TDO will provide additional benefits have been initiated. Prevalence analysis performed by IHC on several conditions indicates that both proteins are highly expressed either on tumor cells or immune cells with important differences among tumor types suggesting the potential for improved efficacy and differentiation of dual IDO1/TDO inhibitors. Our data show for the first time that a dual inhibition of IDO1 and TDO significantly reduces Kyn levels in preclinical tumor models. RG70099 is a potent, dual-selective IDO1 and TDO small molecule inhibitor with favorable pharmaceutical and pharmacokinetic properties that has the potential to relieve immunosuppression by both IDO1 and TDO and activate anti-tumor immune responses for a broad range of cancer types. *IDO1: Indoleamine 2,3-Dioxygenase 1; TDO: Tryptophan 2,3-Dioxygenase Citation Format: Gabor Gyulveszi, Christine Fischer, Massimiliano Mirolo, Martin Stern, Luke Green, Maurizio Ceppi, Haiyan Wang, Beatrice Bürgi, Andreas Staempfli, Wolfgang Muster, Robert van Waterschoot, Andreas Gloge, Hadassah Sade, Irina Klaman, Gabriele Hoelzlvimmer, Arjun Surya, Monali Banerjee, Ritesh Shrivastava, Sandip Middya, Dharmendra Yadav, Sourav Basu, Gonzalo Acuna. RG70099: A novel, highly potent dual IDO1/TDO inhibitor to reverse metabolic suppression of immune cells in the tumor micro-environment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-085.

The cGAS/STING pathway initiates an innate immune response when DNA is detected in the cytosol. DNA bound cGAS synthesizes cyclic dinucleotides which bind and activate the adaptor STING, leading to downstream secretion of Type I interferons and other pro-inflammatory NFκB pathway cytokines. In the mouse, the STING driven innate immune response is central to immune based clearance of various tumors and this has triggered a significant effort focused on the discovery of human STING agonists for the treatment of cancer. This report uses an in vitro kinase assay to show that G10, a previously identified STING pathway activator is actually a weak but direct STING agonist and identifies other more potent leads.

No abstract

No abstract