Phosphonocarboxylate (PC) analogs of the anti-osteoporotic drugs, bisphosphonates, represent the first class of selective inhibitors of Rab geranylgeranyl transferase (RabGGTase, RGGT), an enzyme implicated in several diseases including ovarian, breast and skin cancer. Here we present the synthesis and biological characterization of an extended set of this class of compounds, including lipophilic derivatives of the known RGGT inhibitors. From this new panel of PCs, we have identified an inhibitor of RGGT that is of similar potency as the most active published phosphonocarboxylate, but of higher selectivity towards this enzyme compared to prenyl pyrophosphate synthases. New insights into structural requirements are also presented, showing that only PC analogs of the most potent 3rd generation bisphosphonates inhibit RGGT. In addition, the first phosphonocarboxylate-derived GGPPS inhibitor is reported.
Bibliographical noteCopyright © 2014 Elsevier Masson SAS. All rights reserved.
KMB is grateful for financial support provided by Ministry of Science and Higher Education in Poland (N N204 519839 and IP2010 003070). FPC is grateful for financial support from the Alliance for Better Bone Health. AKN is grateful for support by the graduate school, National Doctoral Programme in Informational and Structural Biology (ISB). This work was supported by the Academy of Finland (252381) fellowship grant, the Sigrid Juselius Foundation, the Cancer Society of Finland and the Marie-Curie Reintegration Grant to DA.
The authors thank Prof. Tadeusz Gajda and Prof. Charles E. McKenna for helpful discussions, Ms. Marzena Kujawa for technical assistance, Jonna Alanko for cloning of the Rab21-NANOPS.