K-Ras is a GTPase that in humans is encoded by the KRAS gene.
An overview of K-Ras
Ras is one member of a large family of small molecular weight GTP-binding proteins. K-Ras function is activated in response to signaling pathways initiated by various extracellular stimuli and results in subsequently binding of numerous effector proteins which promote activation of several signaling cascades within the cell. K-Ras plays an important role in cell proliferation, differentiation, cytoskeletal modulation, and cell survival. K-Ras mutation was found with the highest incidence in pancreatic (90%) and sporadic colorectal carcinomas (50%). The identification of K-Ras as a clinical biomarker and potential therapeutic target has attracted the scientific community to develop effective and precise anticancer drug. The current evidence demonstrates that the expression of an oncogenic form of K-Ras is sufficient to obtain high level of activation in tumor cells, as a result of which mutant K-Ras is considered as potential biomarker and target for precise cancer therapy.
Inhibition of K-Ras
Inhibitors that block the farnesylation of Ras have been developed or are under clinical trial studies. Tipifarnib, approved by USFDA for the treatment of elderly acute leukemia is a Ras pathway inhibitor. Some peptidomimetics and bi-substrate inhibitors like FTI 276, FTI 277, B956, B1086, L731, L735, L739, L750, L778123, BMS-214662,and L778123 are under clinical trials. For the inhibition of K-Ras activity, GGTase-I showed important role by undergoing alternative prenylation with the addition of geranylgeranyl isoprenoid. This isoprenoid substitutes farnesyl group and supports Ras membrane association and transformation. Furthermore, the direct inhibition of K-Ras signaling has not yet led to clinically useful drugs.
K-Ras and diseases
The high incidence of K-Ras mutation has been reported in pancreatic, colon, and lung carcinomas. K-Ras mutations constitute 86% of all Ras mutations and were found to be predominant in the lung, colon, pancreatic cancer and other types of cancer that account for maximal deaths in the United States.
Vivek Asati , Debarshi Kar Mahapatra, Sanjay Kumar Bharti. K-Ras and its inhibitors towards personalized cancer treatment: Pharmacological and structural perspectives. European Journal of Medicinal Chemistry, 2017, 125:299-314.