Calix[4]arene methylenebisphosphonic acids as inhibitors of protein tyrosine phosphatase 1B

Calix[4]arenes bearing methylenebisphosphonic or hydroxymethylenebisphosphonic acid fragments at the wide rim of the macrocycle were studied as inhibitors of PTP1B. Some of the inhibitors showed IC50 values in the micromolar range and good selectivity in comparison with other protein tyrosine phosphatases such as TC-PTP, PTPb, LAR, and CD45. Kinetic studies indicated that the calix[4] arene derivatives influence PTP1B activity as slow-binding inhibitors. Based on molecular docking results, the binding modes of the macrocyclic bisphosphonates in the active centre of PTP1B are discussed. (C) 2013 Elsevier Ltd. All rights reserved.