Structural and Functional Analysis of GGPPS Inhibition as a Therapeutic Mechanism for Acute Myeloid Leukemia (AML).

Acute myeloid leukemia (AML) is a hematological malignancy with poor treatment outcomes and high mortality rates. AML progression is influenced by signalling events facilitated by small GTPases anchored to cellular membranes via post-translational modification with geranylgeranyl pyrophosphate (GGPP). The disruption of GGPP biosynthesis, and the resulting intracellular reduction of key geranylgeranylated GTPases, represents an as yet unleveraged strategy for the treatment of cancer. Here we show compound CML-07-119, a selective inhibitor of GGPP synthase (GGPPS), to display an EC50 potency in the nanomolar range and to induce targeted cell death in several AML cell lines, including those harbouring TP53 mutations. Antitumor efficacy in vivo was also observed with CML-07-119 in a mouse xenograft model engrafted with AML NOMO-1 cells, equivalent to the drug cytarabine. Bone-marrow and splenocyte cells harvested from mice treated with CML-07-119 displayed significantly higher concentration of unprenylated RAP1A as compared to the controls, demonstrating the expected biochemical outcome of in vivo GGPPS inhibition. X-ray crystallography and cryo-EM were used to determine high resolution structures of the unliganded GGPPS and the GGPPS/CML-07-119 complex. These structures revealed that the inhibitor occupies a previously proposed product inhibitory channel of the enzyme, and modulates previously unknown conformational states of GGPPS quaternary structure. This work validates GGPPS inhibition as potential novel mechanism for the treatment of AML.