Ambamustine (PTT-119) is a bifunctional alkylating agent. Its antitumour effect is reported to mainly be through alkylation and interstrand cross-linkage of DNA. The drug was awaiting registration in Italy for the treatment of non-Hodgkin's lymphoma, and was also in phase-II clinical trial for small cell lung cancer, but was discontinued.

GALARUBICIN (DA-125) is an anthracycline derivative with anticancer activity, containing fluorine. The mechanism of action of this drug lies in inhibition of nucleic acid synthesis through intercalation with DNA. Because the structure and DNA-intercalating properties of DA-125 are similar to adriamycin, the cytotoxic effects of the two anthracyclines probably have similar biochemical mechanisms. Preclinical studies suggest that it may have greater activity and less cardiac toxicity than adriamycin. In a rodent study, administration of D-125 in higher dose levels (25 to 50 mg/kg) has been shown to result in testicular damage.

Ametantrone (AM) is a synthetic 9,10-anthracenedione bearing two (hydroxyethylamino)ethylamino residues at positions 1 and 4; along with other anthraquinones and anthracyclines, it shares a polycyclic intercalating moiety and charged side chains that stabilize DNA binding. Ametantrone is anticancer drug candidate targeting DNA. Ametantrone is a topoisomerase II inhibitor of the anthrapyrazole family. Ametantrone induces interstrand DNA cross-links in HeLa S3 cells. These cross-links were observed only in cellular system suggesting that metabolism of the drugs is a necessary step leading to DNA cross-linking. Ametantrone appeared to be very well tolerated and easy to handle. A dose-schedule of 135 mg/m2 q 2–3 weeks was recommended for phase II studies in solid tumors.

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.

Valategrast (R-411) is a dual-acting α4/β1 - α4/β7 integrin antagonist which underwent clinical development with Roche for the treatment of multiple sclerosis (MS) and asthma. Phase I and II studies have been conducted. It had shown good efficacy in animal disease models. Following oral administration, R-411 was rapidly and completely biotransformed into its active metabolite, RO-0270608, most of which was eliminated by biliary excretion. R-411 had shown acceptable pharmacokinetics and good safety in healthy volunteers. R-411 inhibited eosinophil and T H 2 cell excitation and survival, and inhibited eosinophil migration from blood to pulmonary tissues. The idea of combining R-411 with montelukast (leukotriene antagonist) in the pharmaceutical dosage forms, therefore, provided a therapeutic treatment that had the combined effect of reducing circulating eosinophil counts and reducing eosinophil egress into pulmonary tissues, thereby providing an early onset of bronchodilation as well as sustained anti-inflammatory effects. Valategrast had been in phase II clinical trials by Roche for the treatment of asthma and in phase I clinical trials for the treatment of multiple sclerosis (MS). However, the study had been discontinued. Development of Valategrast was discontinued for the treatment of asthma after clarification of the regulatory framework for that class of compounds.

Talisomycin (former trivial name: tallysomycin A), a third generation bleomycin analog that was studied as an antitumor antibiotic. The drug cleaved DNA preferentially at G-C and G-T sequences and produced specific cleavages at G-A sequences. Talisomycin participated in phase II clinical trial for the treatment of cancer; however, the further development of the drug was discontinued.

Millennium Pharmaceuticals Inc's tandutinib (MLN-518), a piperazinyl derivative of quinazoline, is an orally active inhibitor of FLT3 kinase and family members PDGFR beta and c-Kit. Tandutinib inhibited FLT3 phosphorylation, downstream signaling and malignant growth in vitro and in animal models. The drug exhibited limited activity as a single agent in phase I and II clinical trials in patients with AML and myelodysplastic syndrome, but displayed promising antileukemic activity (90% complete remissions) in a phase I/II trial in patients with newly diagnosed AML when administered in combination with cytarabine and daunorubicin. Phase II clinical trials for tandutinib in patients with Glioblastoma have being discontinued. The use of tandutinib to treat AML has been granted fast-track status by the U.S. Food and Drug Administration. Phase II trials were underway., but later withwrawn.

Ethidium is a DNA intercalating agent first discovered as and used as a veterenary trypanocide. A bromide salt is commonly used as a fluorescent tag in molecular biology. The fluorescene of ethidium bromide increased 21 fold upon binding to double-stranded RNA, 25 fold upon binding double stranded DNA. Because of the binding to DNA, ethidium bromide is a powerful inhibitor of DNA polymerase.

Amuvatinib (formerly known as MP470) is an oral multi-targeted tyrosine kinase inhibitor, which play critical roles in transducing growth signals to cancer cells. It suppresses c-MET, c-RET and the mutant forms of cKIT, PDGFR and FLT3. It also disrupts DNA repair likely through suppression of homologous recombination protein Rad51, an important survival pathway in many human cancers. In vitro and in vivo data have demonstrated amuvatinib synergy with DNA damaging agents including etoposide and doxorubicin. Overall, in the amuvatinib clinical development program, over 200 subjects were exposed to at least one dose of amuvatinib. In the Phase 1b clinical study in combination with carboplatin and etoposide, responses in small cell lung cancer (SCLC), neuroendocrine as well as other tumor types were observed. Human pharmacokinetic data suggest that co-administration of amuvatinib did not alter exposures of standard of care agents including carboplatin, etoposide, doxorubicin, paclitaxel, topotecan or erlotinib as measured by overall exposure. In the first-in-human study, durable clinical benefit was observed in the gastrointestinal stromal tumors (GIST) with modulation of Rad51 observed in skin punch biopsies. In clinical trials, amuvatinib has demonstrated a wide therapeutic window and shows minimal toxicity in the expected therapeutic dose range, despite suppressing several signaling pathways within cells. However, in spite of this, this drug was discontinued, because it was not pre-specified primary endpoints in the clinical proof of concept (cPOC) stage. But the combination of MP470 and Erlotinib, which target the HER family/PI3K/Akt pathway may represent a novel therapeutic strategy for prostate cancer.

OSI-7904L is a liposomal formulation of the highly specific, noncompetitive thymidylate synthase inhibitor OSI-7904 (also known as GW1843, BW1843U89, and GS7904). The liposome formulation was developed to enhance the therapeutic index and dose schedule convenience of this potent antifolate compound. This drug was studied in phase II clinical trial in patients to treat head and neck cancer, gastroesophageal adenocarcinoma and advanced biliary cancer, but these studies were discontinued. As an example in case of OSI-7904L, was revealed that its activity was below a level of clinical relevance in advanced biliary tract cancer, providing only a small degree of disease stabilization.