Prenylation Inhibition Strategies in Cancer Therapeutics

Prenylation, the post-translational attachment of isoprenoid lipids to proteins, is essential for localisation and function of small GTPases that drive oncogenic signalling, cell proliferation and survival. Targeting the enzymes that synthesise or transfer these lipid moieties has emerged as a powerful anticancer strategy. Inhibition of farnesyl transferase prevents farnesylation of Ras proteins, disrupting membrane anchoring and downstream MAPK or PI3K signalling. Parallel blockade of geranylgeranyl transferases impairs the function of Rho and Rab GTPases, affecting cytoskeletal dynamics, vesicular trafficking and cell–cell interactions. Upstream in the mevalonate pathway, inhibitors of farnesyl pyrophosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGDPS) deplete the pools of farnesyl and geranylgeranyl pyrophosphate, simultaneously abrogating multiple prenylation-dependent cascades. These approaches have demonstrated antitumour activity in preclinical models and have informed the design of combination regimens with established chemotherapeutics and proteasome inhibitors. Advances in structural biology and chemical biology have yielded novel allosteric inhibitors and bisphosphonate analogues with improved selectivity, pharmacokinetics and safety profiles, opening avenues for precision targeting of prenylation in diverse malignancies.

Research from Nature Portfolio

Recent studies have revealed an allosteric regulatory pocket in human farnesyl pyrophosphate synthase, in which its own product occupies a secondary binding site to lock the enzyme in an inactive conformation. Structural characterisation identified key residues that mediate product-induced feedback inhibition, offering a novel target for small-molecule modulators. Kinetic analyses demonstrated that physiological concentrations of farnesyl pyrophosphate are sufficient to effect allosteric control, underscoring the potency of this mechanism. Exploiting this site may allow precise modulation of isoprenoid levels and targeted disruption of oncogenic prenylation signalling.

Prenylation Inhibition Strategies in Cancer Therapeutics publication trend

The graph below shows the total number of articles in prenylation inhibition strategies in cancer therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Prenylation: The post-translational addition of isoprenoid lipids to proteins, facilitating membrane association and protein–protein interactions.

Farnesylation: Prenylation involving attachment of a 15-carbon farnesyl group, catalysed by farnesyl transferase, crucial for Ras protein function.

Geranylgeranylation: Prenylation involving attachment of a 20-carbon geranylgeranyl group, mediated by geranylgeranyl transferases, essential for Rho and Rab GTPase activity.

Mevalonate pathway: A metabolic cascade producing isoprenoid precursors, including farnesyl and geranylgeranyl pyrophosphate, targeted by statins and prenylation inhibitors.

Small GTPases: A family of signalling proteins (e.g., Ras, Rho, Rab) that require prenylation for membrane localisation and control of proliferative and trafficking pathways.

References

1. Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target. Clinical and Translational Medicine (2023).
2. Human farnesyl pyrophosphate synthase is allosterically inhibited by its own product. Nature Communications (2017).
3. Phosphonate and Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthases: A Structure-Guided Perspective. Frontiers in Chemistry (2021).
4. Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma. Experimental Hematology & Oncology (2022).