New tricks for human farnesyltransferase inhibitor: cancer and beyond

Abstract

Human protein farnesyltransferase (FTase) catalyzes the addition of a C-farnesyl lipid group to the cysteine residue located in the COOH-terminal tetrapeptide motif of a variety of important substrate proteins, including well-known Ras protein superfamily. The farnesylation of Ras protein is required both for its normal physiological function, and for the transforming capacity of its oncogenic mutants. Over the last several decades, FTase inhibitors (FTIs) were developed to disrupt the farnesylation of oncogenic Ras as anti-cancer agents, and some of them have entered cancer clinical investigation. On the other hand, some substrates of FTase were demonstrated to be related with other human diseases, including Hutchinson-Gilford progeria syndrome, chronic hepatitis D, and cardiovascular diseases. In this review, we summarize the roles of FTase in malignant transformation, proliferation, apoptosis, angiogenesis, and metastasis of tumor cells, and the recently anticancer clinical research advances of FTIs. The therapeutic prospect of FTIs on several other human diseases is also discussed.

Single-cell RNA sequencing reveals the tumor microenvironment and facilitates strategic choices to circumvent treatment failure in a chemorefractory bladder cancer patient

“…2a). Tipifarnib is a highly potent and selective farnesyltransferase inhibitor (FTI) that can be particularly effective against advanced MIUBCs harboring mutated HRAS by dramatically attenuating farnesylation-mediated HRAS signaling [47][48][49]. When HRAS activation was pharmacologically inhibited by tipifarnib (50 mg/kg, oral, twice a day), tumor growth was significantly suppressed (Fig.…”

A small molecule inhibitor of Rheb selectively targets mTORC1 signaling

“…However, the lack of selectivity of FTIs, which act on several different GTPases, limits their utility as specific Rheb-targeted agents 27 , 28 . To our knowledge, no small molecules that either directly bind Rheb or specifically modulate Rheb activity have been reported to date.…”

Exploring isoxazoles and pyrrolidinones decorated with the 4,6‐dimethoxy‐1,3,5‐triazine unit as human farnesyltransferase inhibitors

“…Human farnesyltransferase (FTase) inhibitors are appealing compounds, largely studied in oncology to fight cancer and currently investigated for their potentialities to treat other pathologies such as sepsis, Hutchinson–Gilford progeria syndrome, chronic hepatitis D, cardiovascular diseases, or neurodegenerative disorders . Indeed farnesylation of proteins plays a vital role in cell progression .…”