PDBsum entry 4q9z

Transferase/transferase inhibitor

PDB id: 4q9z

Contents

Protein chains

333 a.a.

309 a.a.

Ligands

PZW ×2

Metals

_NA

Waters ×56

PDB id:

4q9z

Name:

Transferase/transferase inhibitor

Title:

Human protein kinasE C theta in complex with compound35 ((1r)-9- (azetidin-3-ylamino)-1,8-dimethyl-3,5-dihydro[1,2,4]triazino[3,4- c][1,4]benzoxazin-2(1h)-one)

Structure:

Human protein kinasE C theta. Chain: a, b. Fragment: kinase domain. Synonym: npkc-theta. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: prkcq, prkct. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.60Å R-factor: 0.220 R-free: 0.256

Authors:

M.A.Argiriadi,D.M.George

Key ref:

D.M.George et al. (2015). Discovery of selective and orally bioavailable protein kinase Cθ (PKCθ) inhibitors from a fragment hit. J Med Chem, 58, 222-236. PubMed id: 25000588 DOI: 10.1021/jm500669m

Date:

02-May-14 Release date: 02-Jul-14

Protein chain

Q04759  (KPCT_HUMAN) -  Protein kinase C theta type from Homo sapiens

Seq: 706 a.a.

Struc: 333 a.a.*

Protein chain

Q04759  (KPCT_HUMAN) -  Protein kinase C theta type from Homo sapiens

Seq: 706 a.a.

Struc: 309 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.2.7.11.13 - protein kinase C.
• 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⁺

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

reference

DOI no: 10.1021/jm500669m

J Med Chem 58:222-236 (2015)

PubMed id: 25000588

Discovery of selective and orally bioavailable protein kinase Cθ (PKCθ) inhibitors from a fragment hit.

D.M.George, E.C.Breinlinger, M.Friedman, Y.Zhang, J.Wang, M.Argiriadi, P.Bansal-Pakala, M.Barth, D.B.Duignan, P.Honore, Q.Lang, S.Mittelstadt, D.Potin, L.Rundell, J.J.Edmunds.

ABSTRACT

Protein kinase Cθ (PKCθ) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKCθ inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.