5T8F

p110delta/p85alpha with taselisib (GDC-0032)

Summary for 5T8F

• Entry DOI: 10.2210/pdb5t8f/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 2-methyl-2-(4-{2-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl}-1H-pyrazol-1-yl)propanamide, ... (4 entities in total)
• Functional Keywords: pi3kdelta kinase, proteros biostructures gmbh, inhibitor, lipid kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm : O00329
• Total number of polymer chains: 2
• Total formula weight: 137527.25

Authors

Moertl, M.,Steinbacher, S.,Eigenbrot, C. (deposition date: 2016-09-07, release date: 2017-01-11, Last modification date: 2023-10-04)

Primary citation

Castanedo, G.M.,Blaquiere, N.,Beresini, M.,Bravo, B.,Brightbill, H.,Chen, J.,Cui, H.F.,Eigenbrot, C.,Everett, C.,Feng, J.,Godemann, R.,Gogol, E.,Hymowitz, S.,Johnson, A.,Kayagaki, N.,Kohli, P.B.,Knuppel, K.,Kraemer, J.,Kruger, S.,Loke, P.,McEwan, P.,Montalbetti, C.,Roberts, D.A.,Smith, M.,Steinbacher, S.,Sujatha-Bhaskar, S.,Takahashi, R.,Wang, X.,Wu, L.C.,Zhang, Y.,Staben, S.T.
Structure-Based Design of Tricyclic NF-kappa B Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K).
J. Med. Chem., 60:627-640, 2017

PubMed Abstract: We report here structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical NF-κB1 (REL-A/p50).

PubMed: 28005357
DOI: 10.1021/acs.jmedchem.6b01363

Experimental method

X-RAY DIFFRACTION (2.91 Å)