7Z61

Crystal structure of PI3Kgamma with a dihydropurinone inhibitor (compound 18)

Summary for 7Z61

• Entry DOI: 10.2210/pdb7z61/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 9-[(3~{R},4~{R})-4-fluoranylpyrrolidin-3-yl]-7-methyl-2-[(7-methylquinolin-6-yl)amino]purin-8-one (2 entities in total)
• Functional Keywords: type i kinase inhibitor, structure-baed drug design, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 111120.52

Authors

Goldberg, F.W.,Ting, A.K.T.,Schimpl, M. (deposition date: 2022-03-10, release date: 2022-07-13, Last modification date: 2024-05-01)

Primary citation

Goldberg, F.W.,Ting, A.K.T.,Beattie, D.,Lamont, G.M.,Fallan, C.,Finlay, M.R.V.,Williamson, B.,Schimpl, M.,Harmer, A.R.,Adeyemi, O.B.,Nordell, P.,Cronin, A.S.,Vazquez-Chantada, M.,Barratt, D.,Ramos-Montoya, A.,Cadogan, E.B.,Davies, B.R.
Optimization of hERG and Pharmacokinetic Properties for Basic Dihydro-8 H -purin-8-one Inhibitors of DNA-PK.
Acs Med.Chem.Lett., 13:1295-1301, 2022

PubMed Abstract: The DNA-PK complex is activated by double-strand DNA breaks and regulates the non-homologous end-joining repair pathway; thus, targeting DNA-PK by inhibiting the DNA-PK catalytic subunit (DNA-PKcs) is potentially a useful therapeutic approach for oncology. A previously reported series of neutral DNA-PKcs inhibitors were modified to incorporate a basic group, with the rationale that increasing the volume of distribution while maintaining good metabolic stability should increase the half-life. However, adding a basic group introduced hERG activity, and basic compounds with modest hERG activity (IC = 10-15 μM) prolonged QTc (time from the start of the Q wave to the end of the T wave, corrected by heart rate) in an anaesthetized guinea pig cardiovascular model. Further optimization was necessary, including modulation of p , to identify compound , which combines low hERG activity (IC = 75 μM) with excellent kinome selectivity and favorable pharmacokinetic properties.

PubMed: 35978693
DOI: 10.1021/acsmedchemlett.2c00172

Experimental method

X-RAY DIFFRACTION (2.738 Å)