CT-2584 is a cytotoxic agent which modulates intracellular metabolism of phosphatidic acid in tumor cells. CT-2884 inhibits CTP:choline-phosphate cytidylyltransferase and causes de novo phospholipid biosynthesis via phosphatidic acid to be shunted away from phosphatidylcholine and into phosphatidylinositol. CT-2884 induced cytotoxicity is associated with disruption and swelling of endoplasmic reticulum and mitochondria. In the early 2000s, CT-2584 was investigated in phase 2 clinical trials for the treatment of prostate cancer and soft-tissue sarcoma. No development of the drug was reported since.

Troxacitabine is a synthetic nucleoside analogue. It is a poor substrate for nucleoside transporters and gains entry into cells by passive diffusion. Intracellular conversion to its active triphosphate form is via deoxycytidine kinase. Incorporation of this metabolite into DNA results in immediate chain termination and apoptosis induction. It is the first nucleoside analog with anticancer activity that has an unnatural stereochemical configuration. The dose-limiting adverse reactions were stomatitis and hand–foot syndrome.

Brivanib is a pyrrolotriazine-based compound and an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) with potential antineoplastic activity. It specifically targets and strongly binds to human VEGFR-2, a tyrosine kinase receptor and pro-angiogenic growth factor expressed almost exclusively on vascular endothelial cells. Blockade of VEGFR-2 by this agent may lead to an inhibition of VEGF-stimulated endothelial cell migration and proliferation, thereby inhibiting tumor angiogenesis. Brivanib has a moderate potency compared to VEGFR-2 against VEGFR-1 and FGFR-1 as well. Brivanib is suggested to be efficient in treatment of hepatocellular carcinoma (HCC). As first-line and as second-line therapy brivanib demonstrated promising antitumor activity and a manageable safety profile in patients with advanced, unresectable HCC in phase II clinical trials. On 3 march 2011, orphan designation was granted by the European Commission to Bristol-Myers Squibb for brivanib alaninate for the treatment of hepatocellular carcinoma.[

Berubicin, an anthracycline derivative, is a DNA binding agent and potent topoisomerase II poison. Reata Pharmaceuticals were developing it as a treatment for brain cancer as it can breach the blood-brain barrier. It had also been in early clinical trials for the treatment of lung cancer and malignant gliomas. However, studies have been terminated. In October 2006, it was granted orphan drug designation from the FDA for the treatment of malignant gliomas. According to a CNS Pharmaceuticals media release in April 2018, berubicin will be studied for glioblastoma patients, these investigations will be funded in part by an equity crowdfunding campaign.

Tasisulam sodium, previously known as LY573636, were initially recognized by Eli Lilly for their significant antiproliferative activities in solid tumor cell lines, but their mechanism of action was unknown. Subsequent studies have revealed that LY573636 induces apoptosis via a mitochondrial-mediated mechanism that appears unique among other anti-cancer compounds. This drug was in the phase III clinical trial for the treatment of Metastatic Melanoma and in phase II for the treatment Non-Small-Cell Lung Cancer, breast cancer, ovarian cancer, but these studies were discontinued. In vivo pharmacokinetic studies in rats and dogs indicate that tasisulam is metabolized primarily by the liver, and has low total plasma clearance with a relatively long half-life. In addition, there was preclinical evidence of a correlation between the maximum plasma concentration (Cmax) of tasisulam and toxicity.

Retaspimycin (IPI-504) was previously under development by manufacturer Infinity Pharmaceuticals in conjunction with MedImmune, a part of AstraZeneca. Retaspimycin is a small-molecule inhibitor of heat shock protein 90 (HSP90) with antiproliferative and antineoplastic activities. Retaspimycin binds to and inhibits the cytosolic chaperone functions of HSP90, which maintains the stability and functional shape of many oncogenic signaling proteins and may be overexpressed or overactive in tumor cells. Retaspimycin-mediated inhibition of HSP90 promotes the proteasomal degradation of oncogenic signaling proteins in susceptible tumor cell populations, which may result in the induction of apoptosis. Orphan drug designation was assigned to the compound by the FDA for the treatment of gastrointestinal stromal cancer (GIST). Infinity Pharmaceuticals has discontinued the development of retaspimycin (IPI-504) an inhibitor of the HSP-90) complex, for the treatment of cancer due to lack of efficacy in 1913.

Tiomolibdic acid salt, Bis-choline tetrathiomolybdate (ATN-224, WTX-101), is under investigation as a therapy against different cancers and Wilson’s disease (WD). ATN-224 is a second-generation analog of ammonium tetrathiomolybdate. ATN-224 is a novel copper chelator. ATN-224 inhibits CuZn superoxide dismutase 1 (SOD1) leading to antiangiogenic and antitumor effects. Strategically tailoring combination regimens that include ATN-224 and target ROS may be a viable approach to advance the treatment of melanoma. ATN-224 is in phase III clinical trial for the treatment of Hepatolenticular degeneration. WTX-101 is in phase II clinical trials for the treatment of Wilson's disease. Once daily WTX-101 treatment over 24 weeks improved neurologic disease, hepatic status and copper control in newly diagnosed WD patients. WTX-101 appears well tolerated. Drug-induced, paradoxical, neurological deterioration was not observed. This compound has received orphan drug designation in both the United States and the European Union. WTX-101 was originally discovered by University of Michigan and now is being developed by Wilson Therapeutics by acquisition.

Obatoclax (GX15-070) is a novel BH3 mimetic pan Bcl- 2 inhibitor. The clinically studied formulation is as obatoclax mesylate (Box 1), a salt. It is only under study as an intravenous preparation. It functions to block BH3-mediated binding of Bcl-2, Bcl-XL, Mcl-1 and A1 to Bax and Bak. Bax and Bak thus are unopposed and able to dimerize to allow initiation of intrinsic apoptosis. Preclinically, obatoclax has been shown to reverse inhibition of Bax or Bak by Bcl-2, Bcl-XL, Bcl-w and Mcl-1. Obatoclax was discovered by Gemin X, which was acquired by Cephalon, which has since been acquired by Teva Pharmaceuticals. Obatoclax had been in phase III clinical trials by Gemin X Biotechnologies (subsidiary of Teva) for the treatment of non-small lung cancer (NSCLC). The compound received orphan drug designation in the U.S. in 2004 for the treatment of chronic lymphocytic leukemia (CLL). However, Teva discontinued the development of obatoclax in 2013.

PF-2545920 is an orally-active phosphodiesterase 10A (PDE10A) inhibitor originated by Pfizer, for the treatment of Huntington's disease. PF-2545920 was originally developed by Pfizer for the treatment of schizophrenia. But later clinical studies for Schizophrenia were discontinued. PF-2545920 is a potent and selective PDE10A inhibitor with IC50 of 0.37 nM, with >1000-fold selectivity over the PDE. PF-2545920 is active in a range of antipsychotic models, antagonizing apomorphine-induced climbing in mice, inhibiting conditioned avoidance responding in both rats and mice, and blocking N-methyl-D-aspartate antagonist-induced deficits in prepulse inhibition of acoustic startle response in rats, while improving baseline sensory gating in mice.

TH9402 is a dibrominated rhodamine derivative and potent photosensitizer and useful in photodynamic therapy. TH9402 preferentially localizes in mitochondria and when exposed to 500- to 600-nm wavelength visible light delivered through the Theralux device, it becomes highly cytotoxic through oxidative damage. TH9402 eradicates multiple myeloma (MM) and BC cell lines, while sparing more than 50% of normal pluripotential blood stem cells from healthy volunteers. TH9402 offers an excellent potential as an ex vivo photodynamic purging agent for autologous transplantation in multiple myeloma and breast cancer treatment. TH9402 photodynamic-cell-therapy process conditions recognized as safe for normal human haematopoietic stem cells and progenitors demonstrated the efficacy of the purging procedure on various leukaemias.