4FAD

Design and Synthesis of a Novel Pyrrolidinyl Pyrido Pyrimidinone Derivative as a Potent Inhibitor of PI3Ka and mTOR

PDB DOI: https://doi.org/10.2210/pdb4FAD/pdb

Classification: Transferase/Transferase Inhibitor
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): No

Deposited: 2012-05-22 Released: 2013-04-03
Deposition Author(s): Greasley, S.E., Knighton, D.R., LaFleur Rogers, C.M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.70 Å
R-Value Free: 0.265
R-Value Work: 0.262
R-Value Observed: 0.262

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Design and synthesis of a novel pyrrolidinyl pyrido pyrimidinone derivative as a potent inhibitor of PI3Kalpha and mTOR

Le, P.T., Cheng, H., Ninkovic, S., Plewe, M., Huang, X., Wang, H., Bagrodia, S., Sun, S., Knighton, D.R., LaFleur Rogers, C.M., Pannifer, A., Greasley, S., Dalvie, D., Zhang, E.

(2012) Bioorg Med Chem Lett 22: 5098-5103

PubMed: 22749419 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2012.05.100
Primary Citation of Related Structures:
4FA6, 4FAD

PubMed Abstract:
Lead optimization efforts that employed structure base drug design and physicochemical property based optimization leading to the discovery of a novel series of 4-methylpyrido pyrimidinone (MPP) are discussed. Synthesis and profile of 1, a PI3Kα/mTOR dual inhibitor, is highlighted.

Organizational Affiliation

Cancer Chemistry, Pfizer Worldwide Research & Development, La Jolla Laboratories, Pfizer Inc., La Jolla, CA 92121, United States. phuong.le@pfizer.com

Macromolecule Content

Total Structure Weight: 111.1 kDa
Atom Count: 6,813
Modelled Residue Count: 839
Deposited Residue Count: 966
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform	A	966	Homo sapiens	Mutation(s): 0 Gene Names: PIK3CG EC: 2.7.1.153 (PDB Primary Data), 2.7.11.1 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P48736 (Homo sapiens) Explore P48736 Go to UniProtKB: P48736
PHAROS: P48736 GTEx: ENSG00000105851
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P48736
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
0TB Query on 0TB Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A]	B [auth A]	2-amino-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-8-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one C₁₈ H₁₉ F N₆ O₂ YJFBSFMYXTWDGD-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]