CYC-116 is a novel, ATP-competitive, pyrimidine drug that is taken by mouth as a capsule. The drug is a selective agent that potently inhibits the enzymes Aurora kinases and VEGFR-2 kinase at comparable levels with a range of 19 to 69 nanomolar. Median potency of CYC-116 in cancer cells is approximately 300 nanomolar. CYC-116 has demonstrated a broad spectrum of potent cytotoxic activity against human tumor cell types. Non-clinical efficacy of CYC-116 has been demonstrated by the oral route using mouse leukemia models, in which increased survival was observed, and human solid tumor xenograft models, in which reductions in tumor growth were observed. Cancer cell types that appear to be particularly sensitive to CYC-116 are leukemia, non-small cell lung cancer and pancreatic cancer. CYC-116 works by affecting the cell cycle progression of cancer cells before they enter mitosis or divide to create daughter cancer cells. The mechanism of action of CYC-116 affects cancer cells in several ways. CYC-116-treated cells display delayed entry into mitosis; defective polymerization of tubulins, or proteins that make up microtubules which are the target of the taxane drugs; changes in the function of the centrosome, or the cell's microtubule organizing center; and formation of the mitotic spindle, or the highway along which chromosomes and cellular materials are transported from the mother cell to the daughter cells. After cancer cells are treated with CYC-116, their spindle checkpoint is inactivated resulting in inhibition of cytokinesis or the process by which a mother cell divides. These defects result in the generation of polyploidy or cells with more than two chromosome sets, multinucleated cells or cells with multiple cores and apoptosis or cancer cell death. In a mouse model of leukemia CYC116-treatment induced decreases in tumor cell volume and infiltration of leukemic cells in the bone marrow and resulted in an increase in life span. No significant effects on body weight or normal bone marrow cells were observed at effective doses of CYC-116. Tumor neovascularization, or creation of new blood vessels around a tumor, was significantly reduced in a dose dependent manner. The data confirm that CYC-116 acts as a dual mitotic and angiogenesis inhibitor, a combination of anti-cancer mechanisms which could have therapeutic benefit in the clinic. CYC-116 is currently being studied in a Phase 1 trial in patients with solid tumors at Roswell Park Cancer Institute in Buffalo, New York, and South Texas Accelerated Research Therapeutics (START) in San Antonio. The study is designed to identify the maximum tolerated dose of CYC-116 and evaluate its pharmacokinetic, pharmacodynamic and anti-tumor effects.

Modipafant is a dihydropyridine derivative patented by American multinational pharmaceutical corporation Pfizer Ltd. as platelet-activating factor antagonist for bronchoconstriction and asthma treatment. Platelet-activating factor, proposed as an important inflammatory mediator in asthma, reproduces several of the features of asthma, such as microvascular leakage, mucus secretion, bronchoconstriction, and possibly increased airway responsiveness. Unfortunately, in clinical trials, Modipafant failed to demonstrate superior efficacy compared to placebo.

Fosbretabulin (Combretastatin A4 phosphate, CA4P) is the lead compound of a relatively new class of agents termed vascular disrupting agents that target existing tumor blood vessels. Rapid tumor blood flow shutdown has been demonstrated in preclinical models and patients by various techniques such as dynamic contrast-enhanced MRI, perfusion computed tomography and PET scans following CA4P infusion. CA4P typically induces rapid tumor necrosis in the center of the tumor and leaves a rim of viable cells in the periphery. In oncology, CA4P does not appear to be that active by itself, but may be more efficacious when combined with chemotherapy, antiangiogenic therapy and radiation therapy. Combretastatin was initially isolated from the root bark of the South African Bush willow Combretum caffrum in 1982 by Pettit and colleagues at the Arizona State University (AZ, USA). Combretastatin A4 phosphate binds avidly to tubulin at the colchicine-binding site to inhibit microtubule assembly and destabilize the cytoskeleton. CA4P is a tubulin-binding agent that binds at or near the colchicine binding site of β-tubulin (Kd = 0.40 uM), inhibits tubulin assembly with IC50 of 2.4 uM. Fosbretabulin has orphan drug status in the EU and the US for the treatment of ATC (Anaplastic Thyroid Cancer). Later the development of this drug was discontinued.

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.

Fandosentan (CI 1034 or PD 180988) is an endothelin A receptor antagonist. It inhibits pulmonary vasoconstriction. Fandosentan was being developed for the treatment of chronic obstructive pulmonary disease and pulmonary hypertension.

GDC-0152 binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2. GDC-0152 promotes degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells. GDC-0152 improves outcome in breast cancer and glioma xenografted mouse. GDC 0512 was in phase I development in the US for the treatment of cancer; however, Roche announced in their 2009 results presentation, that development of the agent has been discontinued.

Tiplasinin (PAI-039) is an orally efficacious and selective plasminogen activator inhibitor-1 (PAI-1) inhibitor. Tiplasinin bound specifically to the active conformation of PAI-1 and exhibited reversible inactivation of PAI-1 in vitro. Tiplaxtinin exhibited in vivo oral efficacy in two different models of acute arterial thrombosis. The remarkable preclinical safety and metabolic stability profiles of tiplaxtinin led to advancing the compound to Phase-I clinical trial for Thrombosis, which was later discontinued.

Piragliatin is a nonessential, mixed-type (i.e. increases maximal velocity and affinity of glucokinase for glucose) small-molecule activators of glucokinase. Preclinical pharmacology studies confirmed that piragliatin had activity in both pancreatic beta-cell and hepatic cell glucose metabolism. Piragliatin augmented glucose-stimulated insulin secretion (GSIS) in human islets from both normal individuals and patients with type 2 diabetes, primarily by left-shifting the glucose dependency curve of GSIS. In healthy volunteers a single administration of piragliatin showed dose-dependent reduction of fasting plasma glucose. The glucokinase activator piragliatin has an acute glucose-lowering action in patients with mild type 2 diabetes, mainly mediated through a generalized enhancement of beta-cell function and through fasting restricted changes in glucose turnover. Headache and mild hypoglycemia were the most frequent adverse events associated with piragliatin treatment. The effect of piragliatin treatment on the QTc interval was dose/exposure dependent following short-term multiple doses. Piragliatin had been in phase II clinical trial for the treatment of Type 2 diabetes mellitus. However, this development was discontinued.

Tilapertin (also known as AMG 747) is a piperazineacetic acid derivative patented by Amgen Inc as glycine transporter-1 inhibitor useful for the treatment of negative symptoms of schizophrenia. Oral administration of AMG 747 dose-dependently increases cerebrospinal fluid(CSF) glycine concentration in rats. In humans, Tilapertin has linear pharmacokinetics, prolonged half-life, and acceptable safety and tolerability at multiple doses up to 60 mg daily dosing. Unfortunately, in clinical trials, Tilapertin failed to demonstrate superior efficacy compare antipsychotic therapy in clinically stable people with schizophrenia.