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[Inhibitors of isoprenylation of ras p21]
1Tsukuba Research Laboratories, Eisai Co., Ltd.
Abstract:
Posttranslational modification and membrane localization are critical for the function of products of ras oncogenes which are frequently founded to be mutated in human tumors. Farnesylation by farnesyltransferase (FTase) is the first and obligatory step in the processing of ras p21, and FTase has attracted attention as a new target of anticancer agents. Many FTase inhibitors have been identified or synthesized in random screening, and studies on FPP analogs, CAAX analogs, and bisubstrate analogs. These inhibitors induced flat reversion and inhibited the anchorage-independent growth of ras transformant and ras-mutated human tumor cells through the inhibition of posttranslational modification of ras p21. B1086, L-739,749, L-744,832 and FTI-276, which are CAAX analogs, were reported to show inhibition of tumor growth in ras-mutated human tumor xenograft models and to induce regression of mammary and salivary carcinoma in ras transgenic mouse model. FTase inhibitors have the potential to be developed as therapy for ras-mutated human tumors. On the other hand, it has been reported that K-ras 4B p21 could be modified by geranylgeranyltransferase (GGTase). Therefore, GGTase inhibitors have also been evaluated in addition to FTase inhibitors.
Insights
Farnesyltransferase (FTase) inhibitors show promise for treating ras-mutated human tumors by blocking ras p21 processing. Research also explores geranylgeranyltransferase (GGTase) inhibitors for similar anticancer effects.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Context:
- Ras oncogenes are frequently mutated in human tumors, impacting cell function.
- Posttranslational modification and membrane localization are crucial for ras oncogene products.
- Farnesylation by farnesyltransferase (FTase) is an essential step in ras p21 processing.
Purpose:
- To explore farnesyltransferase (FTase) inhibitors as potential anticancer agents.
- To evaluate the efficacy of various FTase inhibitors, including CAAX analogs, in preclinical models.
- To investigate geranylgeranyltransferase (GGTase) inhibitors as an alternative or complementary therapy.
Summary:
- FTase inhibitors block the posttranslational modification of ras p21, inhibiting tumor cell growth.
- Specific CAAX analogs (B1086, L-739,749, L-744,832, FTI-276) demonstrated tumor growth inhibition and regression in preclinical models.
- K-ras 4B p21 modification by GGTase suggests GGTase inhibitors are also valuable therapeutic targets.
Impact:
- FTase inhibitors hold potential for developing novel therapies against ras-mutated human tumors.
- These findings support the development of targeted therapies based on inhibiting protein prenylation pathways.
- The study highlights the dual targeting potential of both FTase and GGTase inhibitors in cancer treatment.