6MUL

Murine PI3K delta kinsae domain - cpd 1

Summary for 6MUL

• Entry DOI: 10.2210/pdb6mul/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, 1-{1-[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]piperidin-4-yl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2 entities in total)
• Functional Keywords: phosphoinositide 3-kinase, isoform-specific inhibitors, transferase, inflammatory disorders
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 216564.37

Authors

Fischmann, T.O. (deposition date: 2018-10-23, release date: 2019-05-01, Last modification date: 2023-10-11)

Primary citation

Methot, J.L.,Zhou, H.,Kattar, S.D.,McGowan, M.A.,Wilson, K.,Garcia, Y.,Deng, Y.,Altman, M.,Fradera, X.,Lesburg, C.,Fischmann, T.,Li, C.,Alves, S.,Shah, S.,Fernandez, R.,Goldenblatt, P.,Hill, A.,Shaffer, L.,Chen, D.,Tong, V.,McLeod, R.L.,Yu, H.,Bass, A.,Kemper, R.,Gatto, N.T.,LaFranco-Scheuch, L.,Trotter, B.W.,Guzi, T.,Katz, J.D.
Structure Overhaul Affords a Potent Purine PI3K delta Inhibitor with Improved Tolerability.
J.Med.Chem., 62:4370-4382, 2019

PubMed Abstract: PI3Kδ catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3Kδ inhibitor bearing a benzimidazolone-piperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolone-piperidine selectivity motif. Structure-based design led to the identification of O- and N-linked heterocycloalkyls, with pyrrolidines being particularly ligand efficient and kinome selective, and having an improved safety pharmacology profile. A representative was advanced into a dog tolerability study where it was found to be well tolerated, with no histopathological evidence of vascular injury.

PubMed: 30986068
DOI: 10.1021/acs.jmedchem.8b01818

Experimental method

X-RAY DIFFRACTION (3.09 Å)