PDBsum entry 4o2p

Transferase/transferase inhibitor

PDB id: 4o2p

Contents

Protein chains

265 a.a.

Ligands

11V ×2

Waters ×236

PDB id:

4o2p

Name:

Transferase/transferase inhibitor

Title:

Kinase domain of csrc in complex with a substituted pyrazolopyrimidine

Structure:

Proto-oncogene tyrosine-protein kinase src. Chain: a, b. Fragment: protein kinase domain (unp residues 251-533). Synonym: proto-oncogenE C-src, pp60c-src, p60-src. Engineered: yes

Source:

Gallus gallus. Bantam,chickens. Organism_taxid: 9031. Gene: src, v-src sarcoma viral oncogene. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

2.10Å R-factor: 0.197 R-free: 0.239

Authors:

A.Richters,D.Rauh

Key ref:

C.Tintori et al. (2015). Combining X-ray crystallography and molecular modeling toward the optimization of pyrazolo[3,4-d]pyrimidines as potent c-Src inhibitors active in vivo against neuroblastoma. J Med Chem, 58, 347-361. PubMed id: 25469771 DOI: 10.1021/jm5013159

Date:

17-Dec-13 Release date: 04-Mar-15

Protein chains

P00523  (SRC_CHICK) -  Proto-oncogene tyrosine-protein kinase Src from Gallus gallus

Seq: 533 a.a.

Struc: 265 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

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

Added reference

DOI no: 10.1021/jm5013159

J Med Chem 58:347-361 (2015)

PubMed id: 25469771

Combining X-ray crystallography and molecular modeling toward the optimization of pyrazolo[3,4-d]pyrimidines as potent c-Src inhibitors active in vivo against neuroblastoma.

C.Tintori, A.L.Fallacara, M.Radi, C.Zamperini, E.Dreassi, E.Crespan, G.Maga, S.Schenone, F.Musumeci, C.Brullo, A.Richters, F.Gasparrini, A.Angelucci, C.Festuccia, S.Delle Monache, D.Rauh, M.Botta.

ABSTRACT

c-Src is a tyrosine kinase belonging to the Src-family kinases. It is overexpressed and/or hyperactivated in a variety of cancer cells, thus its inhibition has been predicted to have therapeutic effects in solid tumors. Recently, the pyrazolo[3,4-d]pyrimidine 3 was reported as a dual c-Src/Abl inhibitor. Herein we describe a multidisciplinary drug discovery approach for the optimization of the lead 3 against c-Src. Starting from the X-ray crystal structure of c-Src in complex with 3, Monte Carlo free energy perturbation calculations were applied to guide the design of c-Src inhibitors with improved activities. As a result, the introduction of a meta hydroxyl group on the C4 anilino ring was computed to be particularly favorable. The potency of the synthesized inhibitors was increased with respect to the starting lead 3. The best identified compounds were also found active in the inhibition of neuroblastoma cell proliferation. Furthermore, compound 29 also showed in vivo activity in xenograft model using SH-SY5Y cells.