Structural and Functional Analysis of GGPPS Inhibition as a Therapeutic Mechanism for Acute Myeloid Leukemia
Fraser G. Ferens, Daniel D. Waller, Rebecca Boutin, Hiu-Fung Lee, Mathieu Tremblay, Marc K. Saba-El-Leil, Tian Lai Guan, Kathryn Skorey, Eric Grignano, Michael Sebag, Arun P. Wiita, M. Joanne Lemieux, Youla S. TsantrizosAbstract
Acute myeloid leukemia (AML) is a hematological malignancy with poor treatment options and high mortality rates. AML progression is influenced by signaling events facilitated by small GTPases anchored to cellular membranes via post-translational modification with geranylgeranyl pyrophosphate (GGPP). Herein, we show that CML-07-119, a selective inhibitor of GGPP synthase (GGPPS), exhibits nanomolar potency in blocking the viability of AML cell lines, including cells with TP53 wild-type and TP53 mutations, and has antitumor efficacy in vivo. Bone marrow and splenocytes harvested from mice treated with CML-07-119 displayed significantly higher concentrations of unprenylated RAP1A as compared to the controls, confirming the expected biochemical outcome of in vivo GGPPS inhibition. X-ray crystallography and cryo-EM were used to determine the binding mode of this compound and to identify conformational changes to the GGPPS quaternary structure upon binding of CML-07-119. These studies strongly support GGPPS inhibition as a novel mechanism for the treatment of AML.