PDBsum entry 5dxh

Transferase/transferase inhibitor

PDB id: 5dxh

Contents

Protein chains

989 a.a.

121 a.a.

Ligands

5H2 ×2

PDB id:

5dxh

Name:

Transferase/transferase inhibitor

Title:

P110alpha/p85alpha with compound 5

Structure:

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform. Chain: a, d. 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. Phosphatidylinositol 3-kinase regulatory subunit alpha.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3ca. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Bos taurus. Bovine. Organism_taxid: 9913.

Resolution:

3.00Å R-factor: 0.183 R-free: 0.218

Authors:

T.P.Heffron,R.A.Heald,C.Ndubaku,B.Q.Wei,M.Augustin,S.Do,K.Edgar, C.Eigenbrot,L.Friedman,E.Gancia,P.S.Jackson,G.Jones,A.Kolesnikov, L.B.Lee,J.D.Lesnick,C.Lewis,N.Mclean,M.Mortle,J.Nonomiya,J.Pang, S.Price,W.W.Prior,L.Salphati,S.Sideris,S.Staben,S.Steinbacher, V.Tsui,J.Wallin,D.Sampath,A.Olivero

Key ref:

T.P.Heffron et al. (2016). The Rational Design of Selective Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326). J Med Chem, 59, 985. PubMed id: 26741947 DOI: 10.1021/acs.jmedchem.5b01483

Date:

23-Sep-15 Release date: 27-Jan-16

Protein chains

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

Seq: 1068 a.a.

Struc: 989 a.a.

Protein chains

P23727  (P85A_BOVIN) -  Phosphatidylinositol 3-kinase regulatory subunit alpha from Bos taurus

Seq: 724 a.a.

Struc: 121 a.a.

Enzyme reactions

• Enzyme class 2: Chains A, D: 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⁺
• Enzyme class 3: Chains A, D: E.C.2.7.1.137 - phosphatidylinositol 3-kinase.

Pathway:

• 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 4: Chains A, D: 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 5: Chains B, E: E.C.?

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/acs.jmedchem.5b01483

J Med Chem 59:985 (2016)

PubMed id: 26741947

The Rational Design of Selective Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326).

T.P.Heffron, R.A.Heald, C.Ndubaku, B.Wei, M.Augistin, S.Do, K.Edgar, C.Eigenbrot, L.Friedman, E.Gancia, P.S.Jackson, G.Jones, A.Kolesnikov, L.B.Lee, J.D.Lesnick, C.Lewis, N.McLean, M.Mörtl, J.Nonomiya, J.Pang, S.Price, W.W.Prior, L.Salphati, S.Sideris, S.T.Staben, S.Steinbacher, V.Tsui, J.Wallin, D.Sampath, A.G.Olivero.

ABSTRACT

Inhibitors of the class I phosphoinositide 3-kinase (PI3K) isoform PI3Kα have received substantial attention for their potential use in cancer therapy. Despite the particular attraction of targeting PI3Kα, achieving selectivity for the inhibition of this isoform has proved challenging. Herein we report the discovery of inhibitors of PI3Kα that have selectivity over the other class I isoforms and all other kinases tested. In GDC-0032 (3, taselisib), we previously minimized inhibition of PI3Kβ relative to the other class I insoforms. Subsequently, we extended our efforts to identify PI3Kα-specific inhibitors using PI3Kα crystal structures to inform the design of benzoxazepin inhibitors with selectivity for PI3Kα through interactions with a nonconserved residue. Several molecules selective for PI3Kα relative to the other class I isoforms, as well as other kinases, were identified. Optimization of properties related to drug metabolism then culminated in the identification of the clinical candidate GDC-0326 (4).