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 [1], 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 [2]. 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) [1] and developed a new assay method for high-throughput screening (Arginase Gold™) [3]. 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 polarization ELISA
Fluorescence intensity Surface Plasmon Resonance (SPR)
Chemiluminescence Mass-Spectrometry / LC-MS/MS
TR-FRET (LANCE®) Thermal shift
AlphaLisa®, AlphaScreen®

Literature references

[1] 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

[2] Steggerda MK et al. (2017)  J. Immunother. Cancer. 5, 101.

[3] Manuscript in preparation.

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