8AUP

Structure of hARG1 with a novel inhibitor.

Summary for 8AUP

• Entry DOI: 10.2210/pdb8aup/pdb
• Descriptor: Arginase-1, MANGANESE (II) ION, 2-[(1~{R},3~{R},4~{S})-3-azanyl-3-carboxy-4-[(dimethylamino)methyl]cyclohexyl]ethyl-$l^{3}-oxidanyl-bis(oxidanyl)boron, ... (6 entities in total)
• Functional Keywords: protein-inhibitor complex, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 211315.86

Authors

Napiorkowska-Gromadzka, A.,Nowak, E.,Nowotny, M. (deposition date: 2022-08-25, release date: 2023-03-29, Last modification date: 2024-02-07)

Primary citation

Borek, B.,Nowicka, J.,Gzik, A.,Dziegielewski, M.,Jedrzejczak, K.,Brzezinska, J.,Grzybowski, M.,Stanczak, P.,Pomper, P.,Zagozdzon, A.,Rejczak, T.,Matyszewski, K.,Golebiowski, A.,Olczak, J.,Lisiecki, K.,Tyszkiewicz, M.,Kania, M.,Piasecka, S.,Cabaj, A.,Dera, P.,Mulewski, K.,Chrzanowski, J.,Kusmirek, D.,Sobolewska, E.,Magdycz, M.,Mucha, L.,Masnyk, M.,Golab, J.,Nowotny, M.,Nowak, E.,Napiorkowska-Gromadzka, A.,Pikul, S.,Jazwiec, R.,Dzwonek, K.,Dobrzanski, P.,Meyring, M.,Skowronek, K.,Iwanowski, P.,Zaslona, Z.,Blaszczyk, R.
Arginase 1/2 Inhibitor OATD-02: From Discovery to First-in-man Setup in Cancer Immunotherapy.
Mol.Cancer Ther., 22:807-817, 2023

PubMed Abstract: Pharmacologic inhibition of the controlling immunity pathway enzymes arginases 1 and 2 (ARG1 and ARG2) is a promising strategy for cancer immunotherapy. Here, we report the discovery and development of OATD-02, an orally bioavailable, potent arginases inhibitor. The unique pharmacologic properties of OATD-02 are evidenced by targeting intracellular ARG1 and ARG2, as well as long drug-target residence time, moderate to high volume of distribution, and low clearance, which may jointly provide a weapon against arginase-related tumor immunosuppression and ARG2-dependent tumor cell growth. OATD-02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the other immunomodulators. Completed nonclinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first-in-human clinical study in patients with cancer.

PubMed: 36939275
DOI: 10.1158/1535-7163.MCT-22-0721

Experimental method

X-RAY DIFFRACTION (2.17 Å)