Tosedostat is a proprietary orally bioavailable inhibitor of the M1 family of aminopeptidases with potential antineoplastic activity. Tosedostat is converted intracellularly into a poorly membrane-permeable active metabolite (CHR-79888) which inhibits the M1 family of aminopeptidases, particularly puromycin-sensitive aminopeptidase (PuSA), and leukotriene A4 (LTA4) hydrolase; inhibition of these aminopeptidases in tumor cells may result in amino acid deprivation, inhibition of protein synthesis due to a decrease in the intracellular free amino acid pool, an increase in the level of the proapoptotic protein Noxa, and cell death. There are several ongoing Phase 2 cooperative group-sponsored trials and investigator-sponsored trials evaluating the clinical activity of Tosedostat in combination with standard agents in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

AZD-1208 is an orally available, potent and highly selective Pim inhibitor that effectively inhibits all three isoforms. AZD-1208 inhibits the growth of several AML cell lines and sensitivity correlates with the level of Pim-1 expression, STAT5 activation and presence of protein tyrosine kinase mutation. AZD-1208 causes cell cycle arrest and apoptosis in MOLM-16 cells in culture. This is accompanied by a dose-dependent reduction in phosphorylation of BAD, 4EBP1 and p70S6K. In addition, AZD-1208 leads to potent inhibition of colony growth of primary AML cells from bone marrow aspirates and downregulates phosphorylation of Pim targets. AZD-1208 was in Phase 1 trials to evaluate the safety and tolerability profile and to determine the maximum tolerated dose (MTD). There were two trials where AZD-1208 had been administered orally in AML and solid tumour (of all types) patients. The studies had being discontinued due to safety reasons.

Pevonedistat (MLN4924), discovered by Millennium, is a small molecule inhibitor of the NEDD8-Activating Enzyme (NAE), a key component of the protein homeostasis pathway. MLN4924 is a mechanism-based inhibitor of NAE and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme. The NEDD8-MLN4924 adduct resembles NEDD8 adenylate, the first intermediate in the NAE reaction cycle, but cannot be further utilized in subsequent intraenzyme reactions. The stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by MLN4924. This drug is in phase II clinical trial for the treatment acute myeloid leukemia, chronic myelomonocytic leukemia and myelodysplastic syndromes. In addition in phase I for treatment acute lymphoblastic leukemia. The ability of MLN4924 to cross the blood-brain barrier, its low toxicity, and clinical efficacy in other cancers suggests that this drug is an attractive treatment against glioblastomas.

Troxacitabine is a synthetic nucleoside analogue. It is a poor substrate for nucleoside transporters and gains entry into cells by passive diffusion. Intracellular conversion to its active triphosphate form is via deoxycytidine kinase. Incorporation of this metabolite into DNA results in immediate chain termination and apoptosis induction. It is the first nucleoside analog with anticancer activity that has an unnatural stereochemical configuration. The dose-limiting adverse reactions were stomatitis and hand–foot syndrome.

Zosuquidar (LY-335979) is an experimental antineoplastic drug. It is is a potent modulator of P-glycoprotein-mediated multi-drug resistance with Ki of 60 nM. Zosuqidar was initially characterized by Syntex Corporation, which was acquired by Roche in 1990. Roche licensed the drug to Eli Lilly in 1997. It was granted orphan drug status by the FDA in 2006 for AML. Zosuquidar Trihydrochloride had been in phase III clinical trials by Kanisa Pharmaceuticals for the treatment of acute myeloid leukaemia. However, this research has been discontinued.

Crenolanib is an orally active, highly selective, small molecule, next generation inhibitor of platelet-derived growth factor receptor (PDGFR) tyrosine kinase. Crenolanib, manufactured by Arog Pharmaceuticals in Dallas, is taken orally with chemotherapy. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma. Crenolanib is an orally bioavailable, selective small molecule inhibitor of type III tyrosine kinases with nanomolar potencies against platelet-derived growth factor receptors (PDGFR) (isoforms PDGFRα and PDGFRβ) and Fms-related tyrosine kinase 3 (FLT3). Besides PDGFR and FLT3, crenolanib does not inhibit any other known receptor tyrosine kinase (RTK) (e.g. VEGFR and FGFR) or any other serine/threonine kinase (e.g., Abl, Raf) at clinically achievable concentrations. Preclinical trials have shown Crenolanib to be active in inhibiting both wild-type and mutant FLT3. Crenolanib is cytotoxic to the FLT3/ITD-expressing leukemia cell lines Molm14 and MV411, with IC50s of 7 nM and 8 nM, respectively. In immunoblots, crenolanib inhibited phosphorylation of both the wild-type FLT3 receptor (in SEMK2 cells) and the FLT3/ITD receptor (in Molm14 cells) in culture medium with IC50s of 1-3 nM. Importantly, the IC50 of crenolanib against the D835Y mutated form of FLT3 was 8.8 nM in culture medium. Furthermore, crenolanib had cytotoxic activity against primary samples that were obtained from patients who had developed D835 mutations while receiving FLT3 TKIs. In vitro, the IC50 of crenolanib for inhibition of FLT3/ITD in plasma was found to be 34 nM, indicating a relatively low degree of plasma protein binding. From pharmacokinetic studies of crenolanib in solid tumor patients, steady state trough plasma levels of roughly 500 nM were found to be safe and tolerable, suggesting that crenolanib could potentially inhibit the target in vivo. Crenolanib has no significant activity against c-KIT, which may be an advantage in that myelosuppression can be avoided.1Furthermore, there was no evidence of QTc prolongation in patients treated with crenolanib. In summary, crenolanib offers a number of advantages over other FLT3 TKIs. Clinical trials of crenolanib in AML patients with FLT3 activating mutations are being planned.

Barasertib (AZD1152) is a dihydrogen phosphate prodrug of a pyrazoloquinazoline Aurora kinase inhibitor [AZD1152–hydroxyquinazoline pyrazol anilide (HQPA)] and is converted rapidly to the active AZD1152-HQPA in plasma. AstraZeneca was developing the aurora kinase inhibitor, barasertib (AZD 1152) as a therapeutic for cancer. AZD1152-HQPA is a highly potent and selective inhibitor of Aurora B (Ki, 0.36nmol/L) compared with Aurora A (Ki, 1,369nmol/L) and has a high specificity versus a panel of 50 other kinases. Consistent with inhibition of Aurora B kinase, addition of AZD1152-HQPA to tumour cells in vitro induces chromosome misalignment, prevents cell division, and consequently reduces cell viability and induces apoptosis. Barasertib (AZD1152) potently inhibited the growth of human colon, lung, and haematologic tumour xenografts (mean tumour growth inhibition range, 55% to ≥100%; P < 0.05) in immunodeficient mice. Detailed pharmacodynamic analysis in colorectal SW620 tumour-bearing athymic rats treated i.v. with Barasertib (AZD1152) revealed a temporal sequence of phenotypic events in tumours: transient suppression of histone H3 phosphorylation followed by accumulation of 4N DNA in cells (2.4-fold higher compared with controls) and then an increased proportion of polyploid cells (>4N DNA, 2.3-fold higher compared with controls). Histologic analysis showed aberrant cell division that was concurrent with an increase in apoptosis in AZD1152-treated tumours. Bone marrow analyses revealed transient myelosuppression with the drug that was fully reversible following cessation of Barasertib (AZD1152) treatment. Barasertib (AZD1152) was in phase III for the treatment of Acute myeloid leukaemia, but later these studies were discontinued.

JNJ-28312141 is an orally active colony-stimulating factor-1 receptor and FMS-related receptor tyrosine kinase-3 inhibitor. In preclinical models, JNJ-28312141 caused regression of ITD-FLT3–dependent MV-4-11 AML xenografts. The drug also suppressed the growth of H460 non-small cell lung adenocarcinoma xenografts and inhibited osteoclastogenesis and osteolysis in a rat model of metastatic bone disease.

PIK-75 is a specific inhibitor of the p110 α isoform of phosphatidylinositol-3-kinase, an enzyme which is upregulated in several human cancers. PIK-75 is a p110α inhibitor with IC50 of 5.8 nM (200-fold more potently than p110β), it is also an inhibitor of CDK9. Cell-based assays revealed that PIK-75 potently and dose dependently inhibits in vitro and in vivo production of TNF-alpha and IL-6, diminishes the induced expression of human endothelial cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1), and blocks human monocyte-endothelial cell adhesion. Most importantly, PIK-75, when administered orally in a therapeutic regimen, significantly suppresses the macroscopic and histological abnormalities associated with dextran sulfate sodium-induced murine colitis. The efficacy of PIK-75 in attenuating experimental inflammation is mediated, at least in part, due to the downregulation of pertinent inflammatory mediators in the colon. Collectively, these results provide first evidence that PIK-75 possesses anti-inflammatory potential. Given that PIK-75 is known to exhibit anti-cancer activity, the findings from this study thus reinforce the cross-therapeutic functionality of potential drugs.

There is no available information related any biological and pharmaceutical application of ammonium tetrachlorozincate.