Macrocyclization in the design of a conformationally constrained Grb2 SH2 domain inhibitor.

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Gao Y, Voigt J, Wu JX, Yang D, Burke TR Jr

Macrocyclization in the design of a conformationally constrained Grb2 SH2 domain inhibitor.

Bioorg Med Chem Lett. 2001 Jul 23;11(14):1889-92.

PubMed ID

11459654 [ View in PubMed

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Abstract

Grubbs' olefin metathesis reaction was utilized to prepare a macrocyclic variant of a linear Grb2 SH2 domain antagonist in an attempt to induce a beta-bend conformation known to be required for high affinity binding. In extracellular Grb2 SH2 domain binding assays, the macrocyclic analogue exhibited an approximate 100-fold enhancement in binding potency relative to its linear counterpart. The macrocycle was not as effective in whole cell binding assays as would be expected based on its extracellular binding potency.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
4-[(10s,14s,18s)-18-(2-Amino-2-Oxoethyl)-14-(1-Naphthylmethyl)-8,17,20-Trioxo-7,16,19-Triazaspiro[5.14]Icos-11-En-10-Yl]Benzylphosphonic Acid	Growth factor receptor-bound protein 2	IC 50 (nM)	20	N/A	N/A	Details