New structural insights into Arginase-1, a target for cancer immunotherapy
Oss, November, 29th, 2019 – NTRC scientists have published new insights into the atomic basis of inhibition of the cancer immunotherapy target Arginase-1. Their article, which appeared online this week in the Journal of Structural Biology: X , discloses the crystal structure of Arginase-1 in complex with the clinical compound CB-1158 (INC001158) and the reference inhibitor ABH at different pH values. While Arginase-1 has been a drug target for several decades for vascular and pulmonary diseases, it has recently gained new interest due to the discovery of its role in anti-tumour immune response by its release in the tumour microenvironment by tumour-infiltrating myeloid cells . The therapeutic concept that inhibition of Arginase-1 increases the efficacy of the immune checkpoint inhibitor pembrolizumab (Keytruda®) is currently investigated in clinical trials.
To support new drug discovery on Arginase-1, NTRC scientists resolved the crystal structure of Arginase-1 bound by small molecule inhibitors (Figure 1)  and developed a new assay method for high-throughput screening (Arginase Gold™) . The study in the Journal of Structural Biology: X describes how Arginase-1 adopts slightly different conformations at physiological pH (pH 7.4), and its pH optimum of pH 9.5. Kinetic binding studies via surface plasmon resonance show that CB-1158 has slow association kinetics and a long target residence time. The potent enzyme inhibitory activity of the investigational drug CB-1158 in comparison to earlier inhibitors, such as ABH, is explained by its increased rigidity and additional hydrogen-bond interactions with the protein.
Figure 1. X-ray protein crystal structure of human Arginase-1 with the small molecule inhibitor CB-1158.
The publication in Journal of Structural Biology: X showcases the capabilities of the NTRC team in biochemistry, biophysics and protein X-ray crystallography. NTRC has a hybrid business model, with small molecule drug discovery projects in cancer immunotherapy and Parkinson’s disease. In addition, NTRC provides fee-for-services, by making use of the technology platforms that originally have been developed to support its internal drug discovery projects, such as Oncolines™ and SynergyFinder™ (www.oncolines.com).
Table 1. Summary of NTRC’s capabilities in biochemical and biophysical methods.
|NTRC Precision Medicine Services|
|Technologies for Biochemical Assays||Orthogonal assays|
|Fluorescence intensity||Surface Plasmon Resonance (SPR)|
|Chemiluminescence||Mass-Spectrometry / LC-MS/MS|
|TR-FRET (LANCE®)||Thermal shift|
 Grobben Y, Uitdehaag JCM, Willemsen-Seegers N, Tabak WWA, de Man J, Buijsman RC, and Zaman GJR (2019) Structural insights into human Arginase-1 pH dependence and its inhibition by the small molecule inhibitor CB-1158. Journal of Structural Biology: X, published online, November 26th. https://doi.org/10.1016/j.yjsbx.2019.100014
 Steggerda MK et al. (2017) J. Immunother. Cancer. 5, 101.
 Manuscript in preparation.