Abstract 5555: Discovery of DN-016: A highly potent, selective and orally available IDO1 inhibitor for treating cancers

Abstract

Indoleamine-2,3-dioxygenase (IDO1) is well-recognized as an important target for immunotherapeutic intervention. Growing interests on this target have been demonstrated by the recent expansion of enthusiasms to inhibit the Trp-to-Kyn pathway as a means to control immunosuppression for cancer treatment. Clinical validation of IDO1 inhibitors for treating various tumors including glioblastoma, melanoma, non-small cell lung, pancreatic, and/or breast cancer, as well as metastatic diseases are currently pursued by pharmaceutical companies and other sponsors. These IDO1 inhibitors include several pioneering clinical compounds such as INCB024360 (epacadostat), GDC-0919, indoximod, and BMS-986205, etc. At the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO), it was reported that patients with squamous cell carcinoma of head and neck were responded well to the combinations of epacadostat plus pembrolizumab and epacadostat plus nivolumab. In addition, epacadostat also demonstrated very promising efficacy in combination with PD-1 checkpoint inhibitors for treating various kind of solid tumors. Most recently, at the 32nd SITC annual meeting held in this month, very exciting and encouraging results were just reported by BMS from an early clinical trials for the combo studies of BMS-986205 with Opdivo. Previously we reported a moderately potent IDO1/TDO dual inhibitor DN131 for cancer immunotherapy (AACR2015 Abstract# 4877), herewith we wish to present a much more potent and selective IDO1 inhibitor DN-016 with superior drug-like properties. DN-016 is a novel heterocyclic compound that was discovered through structure-based drug design and medicinal chemistry approaches. In in vitro studies, DN-016 showed very high potency in inhibiting hela IDO1 cell with an IC50 of 0.71 nM. It exhibited good ADME properties and safe hERG parameter with IC50 over 30 μM. Compared to the reference compounds in clinical stages, DN-016 exhibited much superior permeability with excellent efflux ratio (A-B/B-A: 22 × 10-6 cm.s-1 / 24 × 10-6 cm.s-1). In in vivo rat PK studies, DN-016 showed very high oral bioavailability (100% F) when dosing at 10 mg/kg via po. Currently DN-016 is under preclinical evaluation as a single agent and together with a PD-1 inhibitor. In summary, as a new anticancer agent, DN-016 demonstrated a remarkable in vitro potency and selectivity with favorable pharmacokinetic properties. Detailed preclinical evaluation of DN-016 will be presented. Citation Format: Shoujun Chen, Fengtao Liu, Hongli Guo, Shuwen Ren, Yikun Zeng, Wei Yang, Ping Qing, Tao Chen, Feng Zhou, Guocheng Li, Mingliang Sun, Xiaogang Ye, Xingzhong Zhang, Panhu Zhu, Hui Xu, Pei Li, Donghai Li, Zang Jie, Huanping Li, Shuda Zhao, Jiangjing Tan, Heping Yang, Longsheng Wang, Fang Liu, Guangliang Fu, Jianggang Du, Hongye Yang, Wenting Xue, Pei Wang, Lan Guo, Lu Wang, Qun Li, Yuxun Wang, Daxin Gao. Discovery of DN-016: A highly potent, selective and orally available IDO1 inhibitor for treating cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5555.

The immunotherapeutic role of indoleamine 2,3‐dioxygenase in head and neck squamous cell carcinoma: A systematic review

“…An increasing number of new IDO inhibitors are currently being discovered. An example is DN‐016 a highly potent, selective, orally available IDO1 inhibitor with good absorption, distribution, metabolism and excretion and safety profile which was presented at ASCO 2018 10 . Also, HTI 1090 a dual inhibitor of IDO1 and hepatic enzyme tryptophan 2,3‐dioxygenase (TDO) is currently in phase I trial for advanced solid tumours including HNSCC 74 .…”

“…An example is DN‐016 a highly potent, selective, orally available IDO1 inhibitor with good absorption, distribution, metabolism and excretion and safety profile which was presented at ASCO 2018. 10 Also, HTI 1090 a dual inhibitor of IDO1 and hepatic enzyme tryptophan 2,3‐dioxygenase (TDO) is currently in phase I trial for advanced solid tumours including HNSCC. 74 Considered “best in class” IDO1 inhibitor, BMS‐986205 was recently halted from phase III trial 75 but earlier‐phase combination studies are still ongoing.…”

“…However, the vast majority of head and neck cancer patients, about 80%, remain unresponsive to immune checkpoint inhibitor therapy, highlighting the need for more effective immunotherapies and predictive biomarkers 9 . IDO1 inhibitors for melanoma, glioblastoma, NSCLC, pancreatic and breast cancer are under investigation by pharmaceutical companies and sponsors 10 . To date, IDO inhibitors for head and neck cancer have been tested in only several published clinical studies 11‐18 …”

“… 9 IDO1 inhibitors for melanoma, glioblastoma, NSCLC, pancreatic and breast cancer are under investigation by pharmaceutical companies and sponsors. 10 To date, IDO inhibitors for head and neck cancer have been tested in only several published clinical studies. 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 …”

The Role of Metabolism in Tumor Immune Evasion: Novel Approaches to Improve Immunotherapy

“…Other molecules assessed in clinical trials that target IDO are Navoximod, DN1406131, EOS200271 (PF-06840003) [ 126 ], KHK2455, LY01013, MK-7162, SHR9146 (HTI-1090). Additionally, several preclinical studies with novel molecules targeting not only IDO1 but also IDO2 and TDO are being evaluated in cancer as a single agent: DN016 [ 127 ], EPL-1410 [ 128 ], IACS-9779 [ 129 ], RG70099 [ 130 ], TQBWX220 [ 131 ], CMG017 [ 132 ], STB-C017 [ 133 ], and in combination with immunotherapy: DN016 [ 127 ], CMG017, STB-C017 [ 95 , 96 ].…”