Afuresertib (GSK2110183 ) is an orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) with potential antineoplastic activity. Afuresertib binds to and inhibits the activity of Akt, which may result in inhibition of the PI3K/Akt signaling pathway and tumor cell proliferation and the induction of tumor cell apoptosis. Activation of the PI3K/Akt signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K/Akt signaling may contribute to tumor resistance to a variety of antineoplastic agents. Preclinically, AKT inhibition by afuresertib can reverse platinum resistance in ovarian cancer cell lines isolated from patients with platinum-resistant ovarian cancer. Afuresertib is well tolerated and demonstrates clinical activity as monotherapy in heavily pretreated MM patients. Is in phase II clinical trials for Chronic lymphocytic leukaemia; Haematological malignancies; Histiocytosis.

Perifosine is an orally active alkyl-phosphocholine compound with potential antineoplastic activity. Perifosine is an Akt inhibitor, which targets the pleckstrin homology domain of Akt, thereby preventing its translocation to the plasma membrane. Perifosine exerts Akt-dependent and Akt-independent effects, and although many preclinical studies have documented Akt inhibition by perifosine, clinical validation of these findings is lacking. Perifosine is in phase II and III clinical trials for the treatment of neuroblastoma, glioblastoma multiforme and other solid tumors.

Edelfosine is a synthetic alkyl-lysophospholipid, a potent immunomodulator and an effective inhibitor of tumor cell proliferation. The cytotoxic effect of edelfosine has been evaluated in a large variety of both tumor (leukemic and solid) and normal cell types, showing a high degree of selectivity towards tumor cells. Like all alkyl-lysophospholipids, Edelfosine incorporates into the cell membrane and does not target the DNA. In many tumor cells, Edelfosine causes selective apoptosis, sparing healthy cells. Edelfosine can activate the Fas/CD95cell death receptor, can inhibit the MAPK/ERK mitogenic pathway and the Akt/protein kinase B (PKB) survival pathway. Edelfosine apoptosis-inducing abilities were studied with several types of cancer, among them multiple myeloma and non-small and small cell lung carcinoma cell lines. In vivo activity against human solid tumors in mice was shown against malignant gynecological tumor cells, like ovarian cancer, and against breast cancer. In vivo biodistribution studies demonstrated a “considerably higher” accumulation of Edelfosine in tumor cells than in other analyzed organs. Several clinical trials were conducted. Among them, a phase I trials with solid tumors or leukemias and phase II with non-small-cell lung carcinomas (NSCLC). In Phase II clinical trial for use of Edelfosine in treating leukemia with bone marrow transplants, it was found to be safe and 'possibly effective'. A phase II trial for the treatment of brain cancers was also reported. It showed encouraging results in stopping the growth of the tumor and a considerable improvement in the “quality of life” of the patients. A phase II trial on the effect of Edelfosine on advanced non-small-cell bronchogenic carcinoma had a “remarkable” “high proportion of patients with stationary tumor status” as result, stable disease after initial progression in 50% of the patients.

2,5-dimethyl-celecoxib, also known as DMC, is celecoxib analog that lacks COX-2 inhibitory activity but exhibits anti-tumor properties. DMC demonstrated its ability to inhibit xenograft tumor growth through the inhibition of Akt activation. The central mechanism for the anticancer effect of DMC is the suppression of the Wnt/β-catenin signaling pathway. DMS is a synthetic opener of KV7 channels in smooth muscle cells.

AT7867 is a novel and potent inhibitor of both AKT and the downstream kinase p70 S6 kinase (p70S6K) and also of protein kinase A. This ATP-competitive small molecule potently inhibits both AKT and p70S6K activity at the cellular level, as measured by inhibition of GSK3beta and S6 ribosomal protein phosphorylation, and also causes growth inhibition in a range of human cancer cell lines as a single agent. AT7867 inhibited survival and proliferation of established (HT-29, HCT116 and DLD-1 lines) and primary human CRC cells. In vivo, intraperitoneal injection of AT7867 inhibited HT-29 xenograft tumor growth in nude mice. AKT activation was also inhibited in AT7867-treated HT-29 tumors. Together, the preclinical results suggest that AT7867 inhibits CRC cells via AKT-dependent and -independent mechanisms.

A-674563 is a potent, orally available Akt1 inhibitor with an IC50 value of 11nM. Also displays activity against PKA and CDK2 with IC50 values of 16nM and 46nM respectively. A-674563 dose-dependently inhibited survival and proliferation of U937 AML cells and six lines of human AML progenitor cells, yet sparing human peripheral blood mononuclear leukocytes (PBMCs). A-674563 activated caspase-3/9 and apoptosis in the AML cells. intraperitoneal injection of A-674563 at well-tolerated doses suppressed U937 leukemic xenograft tumor growth in nude mice, whiling significantly improving the animal survival. A-674563 exerts potent anti-leukemic activity in vitro and in vivo, possibly via concurrent targeting Akt and SphK1 signalings. A-674563 also exerts potent anti-melanoma activity, involving Akt-dependent and Akt-independent mechanisms.

Trehalose, a naturally occurring disaccharide of glucose that appears to function in an anhydrobiotic capacity in many organisms. Bioblast Pharma study trehalose in Phase 2 for treating patients with Oculopharyngeal Muscular Dystrophy (OPMD) and spinocerebellar ataxia, type 3. In OPMD trehalose prevents the aggregation of the pathological protein (PABPN1) in muscle cells, the hallmark of the disease, by stabilizing the protein, reducing the formation of protein aggregations, and promoting their clearance from cells through autophagy, thus preventing muscle cell death. Trehalose induces autophagy via mTOR independent pathway. It activates TFEB, a master controller of lysosomal biogenesis and autophagy, by inhibiting AKT which is a negative regulator of TFEB that acts by direct phosphorylation (and inhibition) of TFEB. In addition, trehalose protects cells from hypoxic and anoxic injury and suppresses protein aggregation. In vivo studies with trehalose show cellular and behavioral beneficial effects in animal models of neurodegenerative diseases. Trehalose was in phase III clinical trial to study if it was possible to use the drug as add-on therapy in Bipolar Depression. Also in combination with hyaluronate, it can be used to treat dry eye syndrome. Trehalose protects the epithelial cells on the ocular surface, improving their resistance to the daily stresses of dry environments and tear film changes in a dry eye.