MLN9708
Proteasome inhibition constitutes a unique approach to targeted therapy. Inhibition of the proteasome prevents the degradation of numerous regulatory proteins, affecting multiple signaling cascades within the cell.

In vitro, non-clinical studies have shown that proteasome inhibition can be cytotoxic to a variety of cancer cell types. MLN9708 is currently under clinical investigation.

MLN4924
NAE is the E1-activating enzyme for the ubiquitin-like protein Nedd8. NAE catalyzes the first step in the neddylation cascade leading to modification of cullin-based ubiquitin ligase activity. This results in specific protein substrates, with important roles in cancer cell survival, being targeted for degradation.

In preclinical in vivo studies, MLN4924 has been shown to selectively bind to and potentially inhibit NAE. MLN4924 is currently under clinical investigation.

AMG706
Tumor formation and progression correlate with increased signaling through receptor tyrosine kinases, including VEGF receptor family, PDGFR, and c-KIT. Signaling through these kinases has been implicated in cancer cell growth and survival and angiogenesis.

Millennium in collaboration with Amgen, Incorporated, is developing motesanib diphosphate, an investigational small molecule. In preclinical studies, motesanib diphosphate has been shown to bind to and target the VEGF receptor family, PDGFR, and c-KIT. Motesanib diphosphate is currently under clinical investigation.

MLN0518
During tumorigenesis, increased signaling through type three receptor tyrosine kinases, including PDGFR, FLT-3, and c-KIT, is implicated in cancer cell growth and survival and angiogenesis.

In preclinical studies, MLN0518 has been shown to bind to potently inhibit PDGFR, FLT3, c-KIT. MLN0518 is currently under clinical investigation.

TAK-285
Tumor formation and progression correlate with increased signaling through type one receptor tyrosine kinases, including the orphan receptor HER2 and its ligand binding partners EGFR, HER3, and HER4. Signaling through these kinases is implicated in tumor development and malignancy.

In preclinical studies, TAK-285 has been shown to bind to and potently inhibit the type one receptor tyrosine kinases. TAK-285 is currently under clinical investigation.

TAK-701
Tumor formation and progression correlate with increased signaling through the hepatocyte growth factor ligand to the type six receptor tyrosine kinase, MET. Signaling through these kinases has been implicated in cancer cell growth and survival, tumor migration and angiogenesis.

In preclinical studies, TAK-701 has been shown to bind to the ligand inhibit binding of the ligand to the MET receptors. Clinical trials are planned for TAK-701.

TAK-733
Tumor development and malignancy is associated with increased signaling through the type one receptor tyrosine kinases, including the orphan receptor HER2 and its ligand binding partners EGFR, HER3, and HER4. Signaling through type one receptor tyrosine kinases is mediated through the G-protein Ras which associates with the Raf protein to activate the MAP kinase kinase MEK. MEK is thought to in turn activate the MAP kinase ERK which transduces the signal to a variety of effectors leading to cancer progression.

Constitutively active Raf protein is a hallmark of many cancers, and it keeps the pathway active in the absence of mitogen signaling. In preclinical studies, TAK-733 has been shown to bind to and potently inhibit MEK. Clinical trials are planned for TAK-733.

MLN8237
During mitotic cell division, Aurora A is a protein kinase involved in centrosome function and spindle assembly. It is required for faithful chromosome segregation. Aurora A kinase is over-expressed in a wide range of cancers, although significance of this is not known. In vitro, over-expression of Aurora A resulted in neoplastic transformation of certain cell lines, leading to Aurora A kinase's designation as an oncogene.

In preclinical studies, MLN8237 has been shown to selectively bind to and potently inhibit Aurora A kinase. MLN8237 is currently under clinical investigation.

TAK-901
During cell division, Aurora kinase B is thought to play a central role in controlling the proper progression of cells through mitosis by regulating the attachment of the spindles to kinetochores, and the accurate segregation of sister chromatids to each daughter cell.

Aurora kinase B is also thought to function in the separation of daughter cells during cytokinesis. The Aurora kinase genes are over-expressed and amplified in a variety of cancers. The disregulation of the Aurora kinases and their essential roles in cell division make them attractive targets for therapeutic intervention of human cancers. In preclinical studies, TAK-901 has been shown to bind and potentially inhibit Aurora B. Clinical trials are planned for TAK-901.

TAK-700
The progression and growth of prostate cancer cells requires the production of testosterone – the result of a long signaling cascade that begins with secretion of gonadotropin-releasing hormone and lutenizing hormone by cells in the pituitary gland which in turn induce cells in both the adrenal glands and the testes to secrete testosterone which travels to the prostate, stimulating the growth of cancer cells.

While existing therapies target testosterone production in the testes, it is also secreted by cells in the adrenal cortex. Testosterone is synthesized in the mitochondrial membrane of adrenal cells by a series of enzymes including seventeen twenty lyase. In preclinical studies, TAK-700 has been shown to bind to and inhibit the enzyme 17,20 lygase in both the testes and adrenal glands. TAK-700 is currently under clinical investigation.

TAK-683/TAK-448
The progression and growth of prostate cancer cells requires the production of testosterone, the result of a long signaling cascade that begins with secretion of gonadotropin-releasing hormone by neurons in the hypothalamus. The signal leads to the release of adrenocorticotropic hormone and lutenizing hormone by cells in the pituitary gland, which in turn induce cells in both the adrenal glands and the testes to secrete testosterone which travels to the prostate stimulating the growth of cancer cells.

The production of testosterone also completes a feedback loop, ceasing the production of all hormones until testosterone levels diminish again. Gonadotropin releasing hormone is synthesized and secreted by specialized hypothalamic neurons. TAK-683 and TAK-448 are postulated to be agonists of the GPR54 receptor on upstream hypothalamic neurons. Activation of the GPR54 receptor is hypothesized to lead to the transmission of a signal that stimulates downstream neurons to increase the secretion of gonadotropin releasing hormone. Continued stimulation of the GPR54 receptor is thought to result in desensitization of receptor transduction, which is anticipated to result in a complete cessation of the signaling pathway, inhibiting testosterone production. TAK-683 and TAK-448 are currently under clinical investigation.