Receptor tyrosine kinases (RTK) represent a class of high affinity cell surface receptors that play a critical role in the development and progression of several types of cancers. Among the several RTK currently under evaluation as druggable targets for cancer, Mesenchymal epithelial transition factor (c-Met) stands out due to its immense potential in regulating downstream events including cell proliferation, metastases, survival, and apoptosis. c-Met is a proto-oncogene that encodes the protein Met with intrinsic tyrosine kinase activity. Aberrant Met kinase activity triggers a series of unwarranted phosphorylation events and signalling processes that ultimately lead to the development of cancer.

Met kinase expression has also been associated with resistance to EGFR inhibitors with Met amplification reported in lung cancer patients that have acquired resistance to gefitinib or erlotinib. Treatment with Met kinase inhibitors along with EGFR inhibitors in such patients has shown promising results indicating the viability of such combinations. Additionally, inhibition of Met kinase in HER-2 over-expressing breast cancer cells significantly increased the sensitivity to tastuzumab. Recent pre-clinical data indicates the inhibition of HFG/Met signalling pathway as a potential strategy to overcome de novo or acquired resistance encountered with the use of conventional chemotherapeutic agents.

Abnormal activation of Met kinase due to gain-of-function mutations, excessive stimulation by hepatocyte growth factor, amplification and/or over-expression of Met kinase, is implicated in the progression of various cancers such as papillary renal cell carcinoma, head and neck cancer, gastric cancer, colorectal cancer, ovarian cancer, and childhood hepatocellular carcinoma. The HGF/Met signalling pathway thus represents an attractive candidate for targeted cancer therapy.

PI3K-delta, a member of the Class 1 family of phosphoinositide-3 kinases, is predominately expressed in the cells of the hematopoetic system. Deletion of the delta isoform in mice resulted in defective B-cell development indicating the preferential specificity of this isoform for this cell type. Because the isoform contributes to the development, maintenance, transformation, and proliferation of B-cells, targeting PI3K-delta represents a promising approach for the treatment of B-cell malignancies.

Inhibition of the alpha isoform of PI3K, particularly, has been associated with an increased incidence of insulin resistance. The adverse effects observed with alpha inhibitors or pan-PI3K inhibitors thus necessitate the need to develop delta selective inhibitors that would specifically target only a particular lineage of cells without affecting other organs. Because expression of PI3K-delta is limited to blood cells, it serves as an ideal target against cancers associated with dysfunctional expansion of hematopoietic cells.

Recent studies have indicated that genetic inactivation of PI3K-delta function greatly reduces development of Marginal Zone and B-1 cells. While selective loss of PI3K-delta has little impact on mature follicular B cell numbers, the functionality is completely hampered. Although PI3K-delta is also involved in signalling by T cells, mast cells, and other immune cells, PI3K-delta inactivation does not impair the functioning of these cell types possibly due to an overlap of the delta isoform with other PI3K isoforms. On lines with pre-clinical data, high levels of PI3K-delta have been reported in patients with lymphoid tumors. The lack of any activating mutations combined with the moderate cytotoxic effect observed in vitro thus makes PI3K-delta an attractive target for intervention in B-cell leukemias.