4O2P

Kinase domain of cSrc in complex with a substituted pyrazolopyrimidine

Summary for 4O2P

• Entry DOI: 10.2210/pdb4o2p/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, 1-[(2R)-2-chloro-2-phenylethyl]-6-{[2-(morpholin-4-yl)ethyl]sulfanyl}-N-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: pyrazolo-pyrimidine ligand, type i, dfg-in, tyrosine protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Gallus gallus (bantam,chickens)
• Cellular location: Cell membrane : P00523
• Total number of polymer chains: 2
• Total formula weight: 66443.37

Authors

Richters, A.,Rauh, D. (deposition date: 2013-12-17, release date: 2015-03-04, Last modification date: 2023-09-20)

Primary citation

Tintori, C.,Fallacara, A.L.,Radi, M.,Zamperini, C.,Dreassi, E.,Crespan, E.,Maga, G.,Schenone, S.,Musumeci, F.,Brullo, C.,Richters, A.,Gasparrini, F.,Angelucci, A.,Festuccia, C.,Delle Monache, S.,Rauh, D.,Botta, M.
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, 2015

PubMed 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.

PubMed: 25469771
DOI: 10.1021/jm5013159

Experimental method

X-RAY DIFFRACTION (2.1 Å)