Indimitecan, also known as LMP776, is a novel topoisomerase I inhibitor. A substance being studied in the treatment of cancer. It blocks certain enzymes that break and rejoin DNA strands. These enzymes are needed for cells to divide and grow. Blocking them may cause cancer cells to die. Indimitecan (LMP776) also helps anticancer drugs kill cancers that are resistant to some other drugs. LMP776 is a type of indenoisoquinoline and a type of topoisomerase inhibitor. In vitro, LMP776 induces TOP 1 cleavage at unique genomic positions and causes cell cycle arrest in both S and G (2)-M phases. Protein linked DNA breaks were observed in cells treated with nanomolar concentrations of LMP776.

TAK-285 is a novel low-molecular weight compound that was designed, synthesized by Takeda Pharmaceutical Company, Osaka, Japan, and has been shown to selectively and potently inhibit HER2 and EGFR kinase activities. Biochemically, TAK-285 inhibits HER2 and EGFR phosphorylation, with 50% inhibition concentrations of 17 and 23 nmol –1, respectively. This drug was in the phase I of clinical trial for the treatment of solid rumors and cancer but was discontinued due to strategic reasons. In addition was investigated that TAK-285 is not Pgp substrates, which is why it may be useful in the development of agents with the potential to treat brain metastases.

GSK-923295 is a small-molecule inhibitor of the mitotic kinesin centromere-associated protein E (CENP-E), and the third novel drug candidate to arise from Cytokinetics' broad strategic alliance with GlaxoSmithKline (GSK). GSK-923295 demonstrated a broad spectrum of activity against a range of human tumor xenografts grown in nude mice, including models of colon, breast, ovarian, lung and other tumors. GSK-923295 is the first drug candidate to enter human clinical trials that specifically targets CENP-E and is currently in Phase I human clinical trials being conducted by GSK. GSK-923295 inhibited release of inorganic phosphate and stabilized CENP-E motor domain interaction with microtubules. Inhibition of CENP-E motor activity in cultured cells and tumor xenografts caused failure of metaphase chromosome alignment and induced mitotic arrest, indicating that tight binding of CENP-E to microtubules is insufficient to satisfy the mitotic checkpoint. Consistent with genetic studies in mice suggesting that decreased CENP-E function can have a tumor-suppressive effect, inhibition of CENP-E induced tumor cell apoptosis and tumor regression.

(-)-Epigallocatechin is a polyphenol, which occurs naturally in various plants, including green tea leaves. The compound was shown to have anti-cancer activity in vitro, with breast cancer, lung cancer, and colon cancer cells. The commercial preparation of Polyphenon E contains about 3% (-)-epigallocatechin as an impurity.

Daniquidone, also known as Batracylin, is a water-insoluble heterocyclic amide with potential antineoplastic activity. Daniquidone inhibits topoisomerases I and II, thereby inhibiting DNA replication and repair, and RNA and protein synthesis. Batracylin advanced as an anticancer agent to Phase I clinical trials where dose limiting hemorrhagic cystitis (bladder inflammation and bleeding) was observed.

AEE-788 is an orally available anticancer agent that was being developed by Novartis. AEE-788 is a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. At the enzyme level, AEE-788 inhibited EGFR and VEGF receptor tyrosine kinases in the nm range (IC(50)s: EGFR 2 nm, ErbB2 6 nm, KDR 77 nm, and Flt-1 59 nm). In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited (IC(50)s: 11 and 220 nm, respectively). AEE-788 demonstrated antiproliferative activity against a range of EGFR and ErbB2-overexpressing cell lines (including EGFRvIII-dependent lines) and inhibited the proliferation of epidermal growth factor- and VEGF-stimulated human umbilical vein endothelial cells. These properties, combined with a favorable pharmacokinetic profile, were associated with a potent antitumor activity in a number of animal models of cancer, including tumors that overexpress EGFR and or ErbB2. Oral administration of AEE-788 to tumor-bearing mice resulted in high and persistent compound levels in tumor tissue. Moreover, AEE-788 efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. AEE-788 has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters. AEE-788 had been in phase Ⅱ clinical trials by Novartis for the treatment of glioblastoma multiforme. However, this research has been discontinued.

Cedefingol is a derivative of sphingosine, with potential antineoplastic activity. As a sphingosine derivative, cedefingol appears to inhibit protein kinase C (PKC), a kinase that plays an important role in tumorigenesis.

TAK-165 is a new potent inhibitor of human epidermal growth factor receptor 2 (HER2) tyrosine kinase. Mubritinib displays > 4000-fold selectivity over other tyrosine kinases, such as EGFR, FGFR, PDGFR, Jak1, Src and Blk. A Phase I study to investigate a safe dose of Mubritinib, once daily (QD), in patients with tumors known to express HER2 (Breast Neoplasm, Pancreatic Neoplasm, Lung Neoplasm, Ovarian Neoplasm, Renal Neoplasm) has been completed, but appears to have been discontinued, as no new information on the drug has surfaced since December 2008.

Betulinic acid (BA) is a plant-derived pentacyclic triterpenoid that exerts potent anti-cancer effects in vitro and in vivo. It`s anticancer property is linked to its ability to induce apoptotic cell death in cancer cells by triggering the mitochondrial pathway of apoptosis. In contrast to the cytotoxicity of betulinic acid against a variety of cancer types, normal cells and tissue are relatively resistant to betulinic acid, pointing to a therapeutic window. Compounds that exert a direct action on mitochondria present promising experimental cancer therapeutics, since they may trigger cell death under circumstances in which standard chemotherapeutics fail. Thus, mitochondrion-targeted agents such as betulinic acid hold great promise as a novel therapeutic strategy in the treatment of human cancers. Betulinic acid has antiretroviral, antimalarial, and anti-inflammatory properties. Betulinic acid exerts its inhibitory effect by preventing topoisomerase I-DNA interaction as a result of which the 'cleavable complex' is not formed. In consequence, it also acts as an antagonist to camptothecin-mediated cleavage. The antitumor pharmacological effects of BA consist of triggering apoptosis via the mitochondrial pathway, regulating the cell cycle and the angiogenic pathway via factors, including specificity protein transcription factors, cyclin D1 and epidermal growth factor receptor, inhibiting the signal transducer and activator of transcription 3 and nuclear factor‑κB signaling pathways, preventing the invasion and metastasis of tumor cells, and affecting the expression of topoisomerase I, p53 and lamin B1. Betulinic Acid has also been used in trials studying the treatment of Dysplastic Nevus Syndrome. Betulinic acid acts as anti-melanoma agent through inhibiting aminopeptidase N activity with IC50 of 7.3 uM. Betulinic acid is an inhibitor of HIV-1 with EC50 of 1.4 uM.

Falnidamol is an epidermal growth factor receptor inhibitor, developed by Boehringer Ingelheim. Falnidamol demonstrated anticancer activity in vitro. The phase I trial was discontinued due to a dose-limiting increase of liver enzymes, low bioavailability of the drug and the detection of a pharmacologically inactive metabolite.