PDBsum entry 5itd

Transferase/protein transport/inhibitor

PDB id: 5itd

Contents

Protein chains

977 a.a.

249 a.a.

Ligands

6CY

Waters ×20

PDB id:

5itd

Name:

Transferase/protein transport/inhibitor

Title:

Crystal structure of pi3k alpha with pi3k delta inhibitor

Structure:

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform. Chain: a. Synonym: ptdins-3-kinase subunit alpha,phosphatidylinositol 4,5- bisphosphate 3-kinase 110 kda catalytic subunit alpha,p110alpha, phosphoinositide-3-kinase catalytic alpha polypeptide, serine/threonine protein kinase pik3ca. Engineered: yes. Mutation: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3ca. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469. Expression_system_cell_line: tn5. Gene: pik3r1, grb1. Expression_system_cell: tn5

Resolution:

3.02Å R-factor: 0.202 R-free: 0.241

Authors:

M.S.Knapp,R.A.Elling

Key ref:

K.Hoegenauer et al. (2016). Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors. Acs Med Chem Lett, 7, 762-767. PubMed id: 27563400 DOI: 10.1021/acsmedchemlett.6b00119

Date:

16-Mar-16 Release date: 07-Sep-16

Protein chain

P42336  (PK3CA_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform from Homo sapiens

Seq: 1068 a.a.

Struc: 977 a.a.

Protein chain

P27986  (P85A_HUMAN) -  Phosphatidylinositol 3-kinase regulatory subunit alpha from Homo sapiens

Seq: 724 a.a.

Struc: 249 a.a.

Enzyme reactions

• Enzyme class 2: Chain A: E.C.2.7.1.137 - phosphatidylinositol 3-kinase.
• Pathway: 1-Phosphatidyl-myo-inositol Metabolism
• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl- sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H⁺
• Enzyme class 3: Chain A: E.C.2.7.1.153 - phosphatidylinositol-4,5-bisphosphate 3-kinase.

Pathway:

• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5- trisphosphate) + ADP + H⁺
• Enzyme class 4: Chain A: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acsmedchemlett.6b00119

Acs Med Chem Lett 7:762-767 (2016)

PubMed id: 27563400

Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors.

K.Hoegenauer, N.Soldermann, F.Stauffer, P.Furet, N.Graveleau, A.B.Smith, C.Hebach, G.J.Hollingworth, I.Lewis, S.Gutmann, G.Rummel, M.Knapp, R.M.Wolf, J.Blanz, R.Feifel, C.Burkhart, F.Zécri.

ABSTRACT

Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.