c-Met Kinase inhibitors

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.

Click Here For Large ViewAbnormal 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.

Current Status : Late Pre-Clinical

PI3K δ Inhibitors

PI3K δ, 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 δ represents a promising approach for the treatment of B-cell malignancies.

Inhibition of the α isoform of PI3K, particularly, has been associated with an increased incidence of insulin resistance. The adverse effects observed with α 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 δ is limited to blood cells, it serves as an ideal target against cancers associated with dysfunctional expansion of hematopoietic cells.

Click Here For Large ViewRecent 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 δ has little impact on mature follicular B cell numbers, the functionality is completely hampered. Although PI3K δ 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 δ 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 δ an attractive target for intervention in B-cell leukemias.

Current Status : Phase 3 (TGR1202)

PI3K δ/γ Inhibitors

Phosphoinositide-3 kinase (PI3K) belongs to a class of intracellular lipid kinases that phosphorylate the 3 position hydroxyl group of the inositol ring of phosphoinositide lipids (PIs) generating lipid second messengers. While α and δ isoforms are ubiquitous in their distribution, expression of δ and γ is restricted to circulating hematogenous cells and endothelial cells. Unlike PI3K α or PI3K δ, mice lacking expression of PI3K γ or δ do not show any adverse phenotype indicating that targeting of these specific isoforms would not result in any overt toxicity. There is confirmatory evidence on several functional immune cell types being positively influenced by the inhibition of δ and/or γ isoforms in pathological conditions related to hematological cancers. Given their expression profiles, anomalies of PI3K δ/ γ regulation are implicated in diseases arising due to abnormal immune cell expansion and function such as leukemia/lymphomas.

Dual PI3K δ/γ inhibition in Hematological Malignancies

Click Here For Large View The scientific evidence for PI3K involvement, in particular the δ and γ isoforms in various cellular processes stems from studies using small molecule inhibitors and gene-targeting approaches. Although PI3K δ expression has been assigned to B-cells and PI3K γ is associated with T-lymphocytes and neutrophils, there appears to be a significant synergy rather than a redundancy between the two isoforms in various leukemias and lymphomas. In addition dual inhibition is expected to result in better targeted destruction of abnormal lymphocytes. In relapsed/refractory T-cell lymphomas for instance, blockade of the PI3K δ/ γ isoforms at clinically achievable concentrations could potentially prevent T-cell activation/proliferation and alteration of tumor microenvironment with the former attributed to the γ and the latter to the δ isoform. Simultaneous inhibition of PI3K δ/ γ isoforms was shown to prolong survival in a mouse model of T-cell acute lymphoblastic leukemia. Dual targeting of PI3K δ/ γ therefore is strongly implicated as an intervention strategy in leukemias/lymphomas that are hard to treat by conventional means due to the added anti-inflammatory potential that helps modulate the tumor microenvironment.

Current Status : Phase 2
CRAC Channel Inhibitors

Click Here For Large View Calcium Release-activated calcium (CRAC) channels are a sub family of SOCs that are present on the plasma membrane and mediate several functions ranging from gene expression to cell growth. Additionally, they form a network essential for the activation of immune cells that establish the adaptive immune response. The stimulation of plasma membrane receptors activates PLC, which leads to the production of the second messenger IP3. IP3 binds to the IP3R and elicits rapid Ca2+ release from the ER lumen. STIM1 senses Ca2+ decrease in ER and undergoes conformational changes to mediate ORAI gating, which results in Ca2+ influx through ORAI channels. The Ca2+ increase activates NFAT and a number of other transcription factors such as NF‐κB and CREB, among others, which play crucial roles in cancer cells, endothelial cells, cells of the immune system and other non-hematopoietic cells. The blockage of SOCE by CRAC channel inhibitors could suppress tumor growth through the following mechanisms: inhibition of proliferation and metastasis of cancer cells, inhibition of the activation of immune cells that secrete tumor-promoting inflammatory cytokines, inhibition of vascular endothelial cell proliferation, migration, tube formation and angiogenesis. Drugs targeting CRAC channels could therefore be of immense clinical benefit in onco-therapeutics area.

Current Status : Phase 1