Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The demonstration that Ras requires prenylation for its cancer-causing activity led several groups of investigators to an intense search for farnesyltransferase and geranylgeranyltransferase inhibitors as potential anticancer drugs. Rational design of small organic molecules that mimic the carboxyl terminal tetrapeptide prenylation site on Ras resulted in pharmacological agents capable of inhibiting Ras processing and selectively antagonizing oncogenic signaling, and suppressing human tumor growth in mouse models without side effects. These agents presently are undergoing advanced preclinical studies. This review describes the efforts of several groups to design, synthesize and evaluate the biological activities of several classes of prenyltransferase inhibitors. Several important issues, such as mechanism of action of prenyltransferase inhibitors and potential mechanisms of resistance to inhibition of K-Ras farnesylation, are also discussed.
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PMID:Inhibition of Ras prenylation: a novel approach to cancer chemotherapy. 933 18

The development of farnesyltransferase inhibitors, a novel approach to non-cytotoxic anticancer therapy, has been an active area of research over the past decade. Compounds that have advanced to clinical trials were evolved both from substrate-based design efforts and from compound library screening hits. This review focuses on the effort at Merck to evolve inhibitors from the protein substrate of farnesyltransferase, which resulted in the identification of a non-peptide inhibitor for clinical evaluation. X-ray crystal structures of farnesyltransferase complexed with early peptidomimetic as well as later non-peptide inhibitors have validated this design approach. NMR spectroscopic methods for studying enzyme-bound inhibitor structure, in conjunction with the use of conformational constraints, were critical components of subsequent efforts to provide potent inhibitors with varying levels of farnesyltransferase and geranylgeranyltransferase-I inhibitory specificity. Several of these compounds were important tools for investigating the use of prenyltransferase inhibitors to target Ki-Ras-mediated tumor growth.
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PMID:Inhibitors of farnesyltransferase and geranylgeranyltransferase-I for antitumor therapy: substrate-based design, conformational constraint and biological activity. 1276 9

Castrate-Resistant Prostate Cancer (CRPC) is characterized by persistent androgen receptor-driven tumor growth in the apparent absence of systemic androgens. Current evidence suggests that CRPC cells can produce their own androgens from endogenous sterol precursors that act in an intracrine manner to stimulate tumor growth. The mechanisms by which CRPC cells become steroidogenic during tumor progression are not well defined. Herein we describe a novel link between the elevated cholesterol phenotype of CRPC and the TERE1 tumor suppressor protein, a prenyltransferase that synthesizes vitamin K-2, which is a potent endogenous ligand for the SXR nuclear hormone receptor. We show that 50% of primary and metastatic prostate cancer specimens exhibit a loss of TERE1 expression and we establish a correlation between TERE1 expression and cholesterol in the LnCaP-C81 steroidogenic cell model of the CRPC. LnCaP-C81 cells also lack TERE1 protein, and show elevated cholesterol synthetic rates, higher steady state levels of cholesterol, and increased expression of enzymes in the de novo cholesterol biosynthetic pathways than the non-steroidogenic prostate cancer cells. C81 cells also show decreased expression of the SXR nuclear hormone receptor and a panel of directly regulated SXR target genes that govern cholesterol efflux and steroid catabolism. Thus, a combination of increased synthesis, along with decreased efflux and catabolism likely underlies the CRPC phenotype: SXR might coordinately regulate this phenotype. Moreover, TERE1 controls synthesis of vitamin K-2, which is a potent endogenous ligand for SXR activation, strongly suggesting a link between TERE1 levels, K-2 synthesis and SXR target gene regulation. We demonstrate that following ectopic TERE1 expression or induction of endogenous TERE1, the elevated cholesterol levels in C81 cells are reduced. Moreover, reconstitution of TERE1 expression in C81 cells reactivates SXR and switches on a suite of SXR target genes that coordinately promote both cholesterol efflux and androgen catabolism. Thus, loss of TERE1 during tumor progression reduces K-2 levels resulting in reduced transcription of SXR target genes. We propose that TERE1 controls the CPRC phenotype by regulating the endogenous levels of Vitamin K-2 and hence the transcriptional control of a suite of steroidogenic genes via the SXR receptor. These data implicate the TERE1 protein as a previously unrecognized link affecting cholesterol and androgen accumulation that could govern acquisition of the CRPC phenotype.
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PMID:The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes. 2391 67