PDBsum entry 3ml8

Transferase/transferase inhibitor

PDB id: 3ml8

Contents

Protein chain

843 a.a. *

Ligands

ML8

* Residue conservation analysis

PDB id:

3ml8

Name:

Transferase/transferase inhibitor

Title:

Discovery of the highly potent pi3k/mtor dual inhibitor pf-04691502 through structure based drug design

Structure:

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform. Chain: a. Synonym: ptdins-3-kinase subunit gamma, pi3-kinase subunit gamma, pi3k-gamma, phosphatidylinositol-4,5-bisphosphate 3-kinase 110 kda catalytic subunit gamma, ptdins-3-kinase subunit p110-gamma, p120- pi3k. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3cg. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.70Å R-factor: 0.250 R-free: 0.324

Authors:

D.R.Knighton

Key ref:

H.Cheng et al. (2013). Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design. Acs Med Chem Lett, 4, 91-97. PubMed id: 24900568 DOI: 10.1021/ml300309h

Date:

16-Apr-10 Release date: 02-Jun-10

Protein chain

P48736  (PK3CG_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform from Homo sapiens

Seq: 1102 a.a.

Struc: 843 a.a.

Enzyme reactions

• Enzyme class 2: 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: 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: 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: E.C.2.7.1.154 - phosphatidylinositol-4-phosphate 3-kinase.

Pathway:

• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) + 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/ml300309h

Acs Med Chem Lett 4:91-97 (2013)

PubMed id: 24900568

Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design.

H.Cheng, C.Li, S.Bailey, S.M.Baxi, L.Goulet, L.Guo, J.Hoffman, Y.Jiang, T.O.Johnson, T.W.Johnson, D.R.Knighton, J.Li, K.K.Liu, Z.Liu, M.A.Marx, M.Walls, P.A.Wells, M.J.Yin, J.Zhu, M.Zientek.

ABSTRACT

PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.