Amonafide L-malate (AS1413, Xanafide) is a DNA intercalator and topoisomerase II inhibitor that induces apoptosis by disrupting chromatin organisation independently of ATP. This is different from classical topoisomerase II inhibitors which induce apoptosis by causing extensive DNA damage. Amonafide L-malate is also able to evade P-glycoprotein and related transporters that contribute to multi-drug resistance. AS1413 had orphan drug status in both the U.S. and the E.U. for the treatment of AML and also received Fast Track status from the U.S. FDA for the treatment of secondary AML. Amonafide L-malate was originated by Xanthus Pharmaceuticals. It was added to Antisoma's pipeline through the acquisition of Xanthus Pharmaceuticals, Inc. in June 2008. Antisoma discontinued development of Amonafide L-malate after data from the open-label, international Phase III ACCEDE trial in over 420 patients showed that 600 mg/m 2 IV amonafide for 5 days plus cytarabine missed the primary endpoint of significantly improving initial remission rate, defined as the proportion of patients who achieve CR or CRi, vs. daunorubicin plus cytarabine.

Vinepidine, a derivative of vincristine participated in clinical trials as an antineoplastic agent. As a result, the extreme neuromuscular toxicity was observed, that is why this study was discontinued.

Combretastatin A4 is a vascular disrupting agent (VDA) that targets tumor vasculature to inhibit angiogenesis. Combretastatin A4 is a tubulin-binding agent that binds at or near the colchicine binding site of β-tubulin and inhibits tubulin assembly. This tubulin-binding agent was originally isolated from an African shrub, Combretum caffrum. Combretastatin A4 is cytotoxic to umbilical-vein endothelial cells (HUVECs) and to a range of cells derived from primary tumors and these cytotoxicity profiles have been used to assess several novel analogs of the drug for future development. Combretastatin A4 has antitumor activity by inhibiting AKT function. The inhibited AKT activation causes decreased cell proliferation, cell cycle arrest, and reduced in vitro migration/invasiveness and in vivo metastatic ability. Several studies in mice have shown that a single administration of combretastatin A4 (100 mg/kg) does not significantly affect primary tumor growth. However, repeated administration (12.5 – 25.0mg/kg twice daily) for periods of 10 – 20 days resulted in approximately 50% retardation of growth of ectopic Lewis lung carcinoma and substantial growth delay of T138 spontaneous murine breast tumors. In clinical studies, Combretastatin A4 has been well tolerated in patients at doses up to 56 mg/m2, following a protocol of five daily 10-minute intravenous infusions every 21 days. The disodium combretastatin A4 phosphate prodrug is currently undergoing clinical trials in the UK and USA.

Oglufanide, an angiogenesis inhibitor, an immunomodulator, that originally was developed and registered in Russia under the brand name timogen. Oglufanide inhibits vascular endothelial growth factor (VEGF), which may inhibit angiogenesis. This agent has also been reported to stimulate the immune response to hepatitis C virus and intracellular bacterial infections. Oglufanide was studied in the USA for the treatment of cancer, and in September 2001, it was granted Orphan Drug designation for the treatment of ovarian cancer. In addition, in Australia this drug was involved in phase II clinical trial for the treatment of hepatitis C. Oglufanide is also participated in phase III trials for patients with Kaposi's sarcoma, however, this study was discontinued.

Declopramide is an apoptosis inducer. Also, it inhibits NFkappaB activation by inhibition of IkappaBbeta breakdown. In preclinical research, Declopramide demonstrated strong antitumor properties. It had been in phase II clinical trials for the treatment of colorectal cancer. However, this research has been discontinued.

Elacytarabine (CP-4055 or araC-5'elaidic acid ester) is a lipid-conjugated derivative of the nucleoside analog cytarabine. Elacytarabine blocks cell division and may kill cancer cells. It is a type of antimetabolite. It was studied in clinical trials for the treatment of solid tumors. In preclinical and clinical studies, elacytarabine has demonstrated both safety and efficacy in acute myeloid leukemia (AML), with noteworthy activity among the cytarabine-refractory AML population. Elacytarabine was granted orphan drug designation status from the European Commission in 2007 and from the US FDA in 2008, with a fast-track approval designation from the FDA in 2010. Elacytarabine development has been discontinued.

Tozasertib, originally developed as VX-680 by Vertex (Cambridge, MA) and later renamed MK-0457 by Merck (Whitehouse Station, NY), was the first aurora kinase inhibitor to be tested in clinical trials. The drug, a pyrimidine derivative, has affinity for all aurora family members at nanomolar concentrations with inhibitory constant values (Ki(app)) of 0.6, 18, and 4.6 nM for aurora A, aurora B, and aurora C, respectively. Preclinical studies confirmed that tozasertib inhibited both aurora A and aurora B kinase activity, and activity has been reported against prostate, thyroid, ovarian, and oral squamous cancer cell lines. Upon treatment with tozasertib, cells accumulate with a 4N DNA content due to a failure of cytokinesis. This ultimately leads to apoptosis, preferentially in cells with a compromised p53 function. Tozasertib is an anticancer chemotherapeutic pan-aurora kinase (AurK) inhibitor that also inhibits FMS-like tyrosine kinase 3 (FLT3) and Abl. Tozasertib is currently in clinical trials as a potential treatment for acute lymphoblastic leukemia (ALL). In cellular models of cancer, tozasertib activates caspase-3 and PARP and decreases expression of HDAC, increasing apoptosis and inhibiting cell growth. In other cellular models, tozasertib inhibits cell proliferation and metastasis by blocking downstream ERK signaling and downregulating cdc25c and cyclin B. This compound also decreases tumor growth in an in vivo model of prostate cancer.

Canfosfamide is a modified glutathione analogue and nitrogen mustard prodrug, with potential antineoplastic activity. Canfosfamide is selectively activated by glutathione S-transferase P1-1 an enzyme that is over-expressed in many human cancers including ovarian cancer. GST P1-1-mediated cleavage leads to an active cytotoxic phosphorodiamidate alkylating metabolite that forms covalent linkages with nucleophilic centers in tumor cell DNA, which may induce a cellular stress response and cytotoxicity, and decrease tumor cell proliferation. Preclinical studies showed that canfosfamide inhibited the growth and was cytotoxic to a wide range of established cancer cell lines including those derived from ovarian cancer (OVCAR3, HEY, SK-OV-3). Canfosfamide treatment inhibited cancer cell proliferation and induced apoptosis through the activation of the cellular stress response kinase pathway. The cytotoxic activity of canfosfamide correlated with the expression of GST P1-1. Cancer cells in which GST expression levels were increased by transfection with the GST P1-1 gene, were more sensitive to the cytotoxic effects of canfosfamide than the parental cell lines Canfosfamide in combination with pegylated liposomal doxorubicin is well tolerated and active in platinum and paclitaxel refractory or resistant ovarian cancer.

Telatinib (Bay-579352) developed by Bayer is an orally available and highly potent inhibitor of tyrosine kinases VEGFR2,VEGFR3, PDGFR and c-Kit. Telatinib is a potent inhibitor of angiogenesis. Telatinib caused a significant decrease in endothelium-dependent and endothelium-independent vasodilation. Telatinib demonstrates anti-tumor activity in various cancer models. Telatinib is ready for phase III clinical trials for the treatment of gastric cancer. In 2010, it has been granted orphan drug status by the FDA. Most frequent adverse events were pain, nausea, voice changes and fatigue.