6DGT
Selective PI3K beta inhibitor bound to PI3K delta
Summary for 6DGT
| Entry DOI | 10.2210/pdb6dgt/pdb |
| Descriptor | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, 4-[1-(5,8-difluoroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzimidazol-6-yl]-3-fluoropyridin-2-amine (3 entities in total) |
| Functional Keywords | pi3k delta, p110, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 1 |
| Total formula weight | 108110.90 |
| Authors | Somoza, J.,Villasenor, A.,McGrath, M. (deposition date: 2018-05-18, release date: 2018-08-01, Last modification date: 2024-03-13) |
| Primary citation | Chandrasekhar, J.,Dick, R.,Van Veldhuizen, J.,Koditek, D.,Lepist, E.I.,McGrath, M.E.,Patel, L.,Phillips, G.,Sedillo, K.,Somoza, J.R.,Therrien, J.,Till, N.A.,Treiberg, J.,Villasenor, A.G.,Zherebina, Y.,Perreault, S. Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3-Kinase (PI3K) beta Inhibitor. J. Med. Chem., 61:6858-6868, 2018 Cited by PubMed Abstract: Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) β inhibitor, generating a pair of atropisomeric compounds with significantly different pharmacological and pharmacokinetic profiles. Emblematic of these differences, the metabolism of inactive ( M)-28 is primarily due to the cytosolic enzyme aldehyde oxidase, while active ( P)-28 has lower affinity for aldehyde oxidase, resulting in substantially better metabolic stability. Additionally, we report torsional scan and experimental studies used to determine the barriers of rotation of this novel PI3Kβ inhibitor. PubMed: 30015489DOI: 10.1021/acs.jmedchem.8b00797 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.601 Å) |
Structure validation
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