Misonidazole is a nitroimidazole with radiosensitizing and antineoplastic properties. Exhibiting high electron affinity, misonidazole induces the formation of free radicals and depletes radioprotective thiols, thereby sensitizing hypoxic cells to the cytotoxic effects of ionizing radiation. This single-strand breaks in DNA induced by this agent result in the inhibition of DNA synthesis. The drug also possesses a substantial cytotoxic effect, independent of radiation, which is selectively expressed in hypoxic cells. Misonidazole may be cytotoxic to the normal hypoxic tissues in the human body, making this became a major concern in the clinical application of the drug. Misonidazole leads to strand breaks in cellular DNA and those cells which fail to survive also fail to repair these strand breaks. Misonidazole depletes intracellular glutathione and is more toxic in glutathione depleted cells.

Lometrexol, formerly known as DDATHF; LY 264618; T-64 was the first glycinamide ribonucleotide formyl transferase (GARFT) inhibitor to be investigated clinically. Lometrexol had been in phase II clinical trial for the treatment non-small cell lung cancer (NSCLC). However, the studies have been discontinued by Tularik Inc, because Company had suggested, that drug would face competition from other companies in the indication

Methoxyamine (TRC102) is an orally bioavailable small molecule with potential adjuvant activity, that may potentiate the antitumor activity of alkylating agents. Methoxyamine covalently binds to apurinic/apyrimidinic (AP) DNA damage sites and inhibits base excision repair (BER) that causes topoisomerase II-dependent irreversible strand breaks and apoptosis. Methoxyamine is currently being studied in multiple Phase 1 and Phase 2 clinical trials sponsored by the National Cancer Institute or Case Comprehensive Cancer Center.

Tivantinib (ARQ 197) is the first non-ATP-competitive small molecule that selectively targets the c-Met receptor tyrosine kinase. Exposure to Tivantinib resulted in the inhibition of proliferation of c-Met-expressing cancer cell lines as well as the induction of caspase-dependent apoptosis in cell lines with constitutive c-Met activity. ArQule and its collaborators Daiichi Sankyo and Kyowa Hakko Kirin are developing tivantinib as a potential therapy for many cancers. c-Met is overexpressed in many cancers. Tivantinib currently is in phase 3 clinical development for the treatment of hepatocellular carcinoma and non-small cell lung cancer.

Salirasib or S-trans,trans-Farnesylthiosalicylic acid (FTS) is a salicylic acid derivative with potential antineoplastic activity. It acts as a potent competitive inhibitor of the enzyme prenylated protein methyltransferase (PPMTase), which methylates the carboxyl-terminal S-prenylcysteine in a large number of prenylated proteins including Ras. In such systems, Salirasib inhibits Ras methylation but not Ras farnesylation. Salirasib selectively disrupts the association of chronically active Ras proteins with the plasma membrane. Salirasib competes with Ras for binding to Ras-escort proteins, which possess putative farnesyl-binding domains and interact only with the activated form of Ras proteins, thereby promoting Ras nanoclusterization in the plasma membrane and robust signals. Salirasib was studied in the clinical trials in patients with solid tumors, however its development was discontinued.

Vadimezan (5,6-dimethyl(xanthenone-4-acetic acid), ASA404, DMXAA) is a fused tricyclic analogue of flavone acetic acid with potential antineoplastic activity. In pre-clinical mouse tumour models it was demonstrated that administration of Vadimezan rapidly leads to disruption of the existing vasculature in the tumour and consequent haemorrhagic necrosis of the tumour. This was consistent with the finding that a single dose of Vadimezan induced a prolonged reduction in the growth of xenografted tumours in animal models. The ability to disrupt the vasculature in these pre-clinical models has been attributed to a rapid induction of cytokines, particularly TNFα (tumour necrosis factor α), serotonin and nitric oxide, resulting in hemorrhagic necrosis and a decrease in angiogenesis. Despite the fact that the molecular targets for the drug remained unknown, the promising pre-clinical results led to Vadimezan being selected for clinical development. Results of Phase I trials showed some restriction of tumour blood flow within 24 h of treatment, although this was not as dramatic as seen in pre-clinical models. Unlike the animal models, there was also very little evidence for the rapid death of blood vessels or for increases in TNFα levels in human tumors. No difference in antitumour activity, cytokine induction or toxicity was observed between two parallel Phase I trials, one dosed weekly and the other dosed every 3 weeks. Therefore the drug proceeded to Phase II clinical trials, dosed every 21 days in combination with chemotherapeutic agents. These trials indicated the drug had small benefits in the treatment of non-small-cell lung cancer and prostate cancer. However, a subsequent Phase III clinical trial was not able to reproduce this response and clinical development was halted.

Zibotentan (ZD4054) is a potent and specific orally available endothelin A (ETA) receptor antagonist, with no measurable affinity for endothelin B receptor. Activation of the ETA receptor by ET-1 has emerged as an important factor promoting tumor cell proliferation, survival, angiogenesis, migration, invasion, and metastasis in several tumor types. Zibotentan inhibits endothelin-mediated mechanisms that promote tumour cell proliferation. Zibotentan was being developed by AstraZeneca as treatment for heart failure, hormone resistant prostate cancer and other cancers including non-small cell lung, ovarian and breast cancer. However, following disappointing results from a phase III trial in patients with advanced prostate cancer, AstraZeneca decided to discontinue the development of zibotentan as a potential treatment for cancer. AstraZeneca undertook preclinical studies in the UK with zibotentan to investigate its potential as a treatment for heart failure. However, development for this indication has been discontinued.

Pfizer's CP-547632 is a selective inhibitor of VEGFR-2 tyrosine kinase that was discovered during Pfizer's collaboration with OSI Pharmaceuticals. CP-547632, was identified as a potent inhibitor of the VEGFR-2 and basic fibroblast growth factor (FGF) kinases (IC(50) = 11 and 9 nM, respectively). It is selective relative to epidermal growth factor receptor, platelet-derived growth factor beta, and other related TKs. It also inhibits VEGF-stimulated autophosphorylation of VEGFR-2 in a whole cell assay with an IC(50) value of 6 nM. After oral administration of CP-547632 to mice bearing NIH3T3/H-ras tumors, VEGFR-2 phosphorylation in tumors was inhibited in a dose-dependent fashion (EC(50) = 590 ng/ml). CP-547,632 is a well-tolerated, orally-bioavailable inhibitor presently under clinical investigation for the treatment of human malignancies. CP-547632 is in phase I for the treatment of diabetic retinopathy and age-related macular degeneration.

Entinostat (MS-275) is an orally active, highly selective, small-molecule histone deacetylase inhibitor (HDACi) derived from benzamide. Entinostat preferentially inhibited HDAC1 versus HDAC3 and had no inhibitory activity toward HDAC8. The time to maximum plasma concentration (tmax) of entinostat ranged from 0.5 to 60h (median of 2h). Elimination of the drug was bi-exponential, with a terminal half-life of 30-80h. Entinostat is a well-tolerated that demonstrates promising therapeutic potential in both solid and hematologic malignancies. Its efficacy does not appear directly dose-related, and as such, more relevant biomarkers are needed to adequately assess its activity.

Marimastat is a broad spectrum matrix metalloprotease (MMP) inhibitor. It is an angiogenesis and metastasis inhibitor. It mimics the peptide structure of natural MMP substrates and binds to matrix metalloproteases, thereby preventing the degradation of the basement membrane by these proteases. This antiprotease action prevents the migration of endothelial cells needed to form new blood vessels. Inhibition of MMPs also prevents the entry and exit of tumor cells into existing blood cells, thereby preventing metastasis. Marimastat has been in pivotal phase III trials in glioblastoma, breast, ovarian and small and non-small cell lung cancer, but these trials have all been discontinued because marimastat failed to show superior efficacy over either standard chemotherapy or placebo.