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.

Imiloxan is a highly selective alpha2B adrenoceptor antagonist and was developed for depression in the 1980s. In Phase 1 clinical trials imiloxan dosing led to hypersensitivity reactions; the molecule's development was discontinued.

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.

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.

Denbufylline is a selective xanthine derivative that inhibits PDE IV and has bronchodilatory properties. Shown to exhibit negative inotropic effects by acting on verapamil-sensitive sites of Ca2+ channels in guinea pig ventricle papillary muscle independently of its PDE inhibitory activity. Denbufylline, a selective type 4 phosphodiesterase (PDE-4) inhibitor, is a potent activator of the hypothalamo-pituitary-adrenal (HPA) axis when given orally or intraperitoneally (i.p.) to adult male rats. Denbufylline was being developed as an agent for the therapy of dementia.

AstraZeneca was developing AZD-7762 for the treatment of solid tumours. AZD-7762 is a potent inhibitor of Chk1 that binds in the ATP binding pocket (IC50 of 5nM; Ki of 3.6nM). AZD-7762 has activity on a range of other kinases {examples with a < 5 fold selectivity included Rous sarcoma oncogene cellular homolog (SRC) family members (e.g., Fgr, Fyn, lymphocyte-specific protein-tyrosine kinase [Lck], and Lyn, but not SRC), Flt1/3, colony stimulating factor receptor (CSF1R), RET, Abelson tyrosine kinase (Abl), and checkpoint kinase 2 (Chk2)}. It is not known if these in vitro kinase inhibitions translate into an effect in vivo. In combination with DNA-damaging agents (gemcitabine, topotecan, doxorubicin, and cisplatin), AZD-7762 inhibits tumour cell growth in vitro with a mode of action that correlates with Chk1 inhibition and abrogation of the Gap 2 (G2) and S phase checkpoints. Rightward shifts in 50% growth inhibition (GI50) values over DNA-damaging agents alone ranged from 5- to 20-fold with gemcitabine demonstrating the largest shifts followed by topotecan. In combination with radiation, AZD-7762 enhances tumour cell growth inhibition and death with survival enhancement ratios ranging from 1.7 to 1.9. Triple combinations with AZD-7762, gemcitabine, and radiation yield the largest survival enhancement ratios. AZD-7762 had been in phase I clinical trials by AstraZeneca for the treatment of solid tumors. However, this study was terminated for the safety reason in 2011.

E7107 is a semisynthetic derivative of the natural product pladienolide B which was originally isolated from Streptomyces platensis. E7107 is the first compound a new class of anti-cancer agents targeting the spliceosome. Specifically E7107 interacts with the Splicing factor 3B subunit 1 (SF3b1) to block the normal splicing of oncogenes. Development of E7107 was suspended after Phase I clinical trials due to an unacceptable profile of adverse events.

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.

Diclofensine is an antidepressant with equipotent inhibitive effects on the neuronal uptake of norepinephrine (NE), serotonin, and dopamine. It is devoid of monoamine-releasing or monoaminoxidase-inhibiting properties. Diclofensine was found to be an effective antidepressant in human trials, with relatively few side effects, but was ultimately dropped from clinical development.