Covalent inhibition of the lymphoid tyrosine phosphatase

Abstract

Covalent inhibitors of lymphoid tyrosine phosphatase (LYP) were identified from a screen of the NIH Molecular Libraries Small Molecules Repository (MLSMR). Both of the two lead compounds identified have phosphotyrosine-mimetic benzoic acid moieties as well as electrophilic acrylonitrile groups. Inhibition kinetics of both compounds are consistent with covalent modification of the enzyme, with nanomolar KI and reciprocal millisecond kinact values, representing the best efficiency ratios (kinact /KI ) among currently reported covalent LYP inhibitors. Covalent inhibitors can provide longer efficacy and better selectivity than more conventional noncovalent inhibitors, and these lead compounds are an important step toward the development of protein tyrosine phosphatase (PTP)-targeted covalent therapeutic compounds.

Keywords: LYP; PTP; acrylonitriles; electrophiles; irreversible inhibitors; phosphatases.

Figure 1

Structures of two electrophilic compounds with activity as covalent LYP inhibitors.

Figure 2

Time dependent inhibition of LYP by compound 1 (selected progress curves, left panel) and a fit of the k_obs data to obtain K_I and k_inact (right panel).

Figure 2

Time dependent inhibition of LYP by compound 1 (selected progress curves, left panel) and a fit of the k_obs data to obtain K_I and k_inact (right panel).

Figure 3

Time dependent inhibition of LYP by compound 2 (selected progress curves, left panel) and a fit of the k_obs data to obtain K_I and k_inact (right panel).

Figure 3

Time dependent inhibition of LYP by compound 2 (selected progress curves, left panel) and a fit of the k_obs data to obtain K_I and k_inact (right panel).

Scheme 1

Equation illustrating the irreversible inhibition of an enzyme.