Motesanib (AMG 706), a novel nicotinamide, was identified as a potent, orally bioavailable inhibitor of the VEGFR1/Flt1, VEGFR2/kinase domain receptor/Flk-1, VEGFR3/Flt4 and Kit receptors. Motesanib was expected to reduce vascular permeability and blood flow in human tumours. A phase III trial of motesanib in combination with paclitaxel and carboplatin in non-squamous NSCLC has been terminated by Takeda and subsequently the development was discontinued. Motesanib has also been investigated up to phase II in breast, thyroid, colorectal and gastrointestinal stromal tumours. However, development has been discontinued in these indications.

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.

Dutogliptin (PHX-1149T) is a small-molecule dipeptidyl peptidase-4 (DPP-4) inhibitor for the potential oral treatment of type 2 diabetes mellitus (T2DM). DPP-4 quickly degrades the insulin secretory hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1; thus inhibiting the degradation of these hormones is a viable treatment option for patients with T2DM. In preclinical studies, dutogliptin potently inhibited DPP-4 and, in a model of T2DM, treatment with dutogliptin improved glucose homeostasis. Pharmacokinetic analyses in animals, healthy individuals and patients with T2DM demonstrated that drug exposure increased in a dose-dependent manner. Results from phase II clinical trials indicated that once-daily dutogliptin, in combination with other oral diabetes therapies, reduces postprandial blood glucose and HbA1c levels, both indicators of successful diabetes management. The incidence of adverse events was similar in treatment and placebo groups, with slightly more headache, arthralgia, sinusitis, and dizziness occurring in the 400 mg dutogliptin group compared with placebo. Phase II clinical trial for the myocardial infarction treatment is underway.

Mocetinostat is an rationally designed, orally available, Class 1-selective, small molecule, 2-aminobenzamide HDAC inhibitor with potential antineoplastic activity. Mocetinostat binds to and inhibits Class 1 isoforms of HDAC, specifically HDAC 1, 2 and 3, which may result in epigenetic changes in tumor cells and so tumor cell death; although the exact mechanism has yet to be defined, tumor cell death may occur through the induction of apoptosis, differentiation, cell cycle arrest, inhibition of DNA repair, upregulation of tumor suppressors, down regulation of growth factors, oxidative stress, and autophagy, among others. It is undergoing clinical trials for treatment of various cancers including bladder cancer, diffuse large B cell lymphoma, follicular lymphoma, myelodysplastic syndromes, non-small cell lung cancer. Fatigue, weight loss or anorexia were most common treatment-related adverse events.

Furegrelate (previously known as U-63557A), a selective orally active thromboxane synthase inhibitor, with potential for the treatment of various diseases including hypertension, thrombosis, and renal disorders, arrhythmias, but these studies were discontinued.

Afuresertib (GSK2110183 ) is an orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) with potential antineoplastic activity. Afuresertib binds to and inhibits the activity of Akt, which may result in inhibition of the PI3K/Akt signaling pathway and tumor cell proliferation and the induction of tumor cell apoptosis. Activation of the PI3K/Akt signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K/Akt signaling may contribute to tumor resistance to a variety of antineoplastic agents. Preclinically, AKT inhibition by afuresertib can reverse platinum resistance in ovarian cancer cell lines isolated from patients with platinum-resistant ovarian cancer. Afuresertib is well tolerated and demonstrates clinical activity as monotherapy in heavily pretreated MM patients. Is in phase II clinical trials for Chronic lymphocytic leukaemia; Haematological malignancies; Histiocytosis.

Ezatiostat (TLK199) [γ-glutamyl-S-(benzyl)cysteinyl-R-phenyl glycine diethyl ester] is an inhibitor of Glutathione S-transferase P1–1 (GSTπ). The drug is a peptidomimetic of GSH (glutathione), esterified to enhance cellular uptake and designed to bind to the “G-site” of GSTP1–1. Independent of catalysis inhibition, TLK199 also disrupts the protein:protein interaction site(s) between GSTP1–1 and JNK1. Telik Inc was developing TLK-199 for the potential prevention of myelosuppression in blood diseases, namely myelodysplastic syndrome.

Abexinostat (PCI-24781) is a novel, second-generation phenyl hydroxamic acid–based, orally bioavailable HDAC inhibitor that has previously been shown to have activity in vitro and in vivo against a broad array of cancers, including hematopoietic malignancies and bone and soft-tissue sarcomas. Abexinostat is a pan-HDAC inhibitor mostly targeting HDAC1 with Ki of 7 nM, modest potent to HDACs 2, 3, 6, and 10 and greater than 40-fold selectivity against HDAC8. Abexinostat exhibits potent antitumor activity against a variety of tumor cell lines with GI50 ranging from 0.15 uM to 3.09 uM. PCI-24781 also has an antiproliferative effect on HUVEC endothelial cells with GI50 of 0.43 uM. Abexinostat treatment causes dose-dependent accumulation of both acetylated histones and acetylated tubulin in HCT116 or DLD-1 cells, induces expression of p21, and leads to PARP cleavage and accumulation of the γH2AX. It has also shown good tolerability and activity in Phase I and II clinical trials against lymphoma, as well as against solid tumors in Phase-I trials. Additionally, it acts as a potent radiosensitizing agent and is synergistic with cytotoxic chemotherapy, such as doxorubicin in preclinical models.

Dalvastatin is a synthetic HMG-CoA reductase inhibitor developed by Rhône-Poulenc Rorer. Dalvastatin is a prodrug and is itself an inactive lactone. After oral ingestion, the drug is hydrolyzed in vivo to the corresponding beta-hydroxy acid, which is the pharmacologically active form. HMG-CoA reductase is the rate-limiting enzyme in the cholesterol biosynthetic pathway. An active form of dalvastatin inhibits HMG-CoA reductase with IC50 of 3.4 nM. In ex vivo assay, orally administered dalvastatin inhibited cholesterol biosynthesis in rat liver slices with an ED50 value of 0.9. The efficacy of dalvastatin to lower cholesterol was investigated in the clinical trials in the 1990s, but no results were reported.

Sotrastaurin, an orally-active, first-in-class immunomodulator, is under development by Novartis for the treatment of uveal melanoma and diffuse-large B-cell lymphoma. Sotrastaurin is a low molecular mass synthetic compound that potently inhibits the PKC α, β and the θ isoforms resulting in selective NF-κB inactivation. Sotrastaurin is a potent and selective pan-PKC inhibitor, mostly for PKCθ with Ki of 0.22 nM in a cell-free assay. Inhibition of PKC beta in B-cells results in prevention of NF-kB-mediated signaling and down regulation of NF-kB target genes. This may eventually lead to an induction of G1 cell cycle arrest and tumor cell apoptosis in susceptible tumor cells. This agent may act synergistically with other chemotherapeutic agents. PKC, a family of serine/threonine protein kinases overexpressed in certain types of cancer cells, is involved in cell differentiation, mitogenesis, inflammation, and the activation and survival of lymphocytes. Sotrastaurin is currently in phase II trials by Novartis for the treatment of large B-cell lymphoma and uveal melanoma. Sotrastaurin was in Phase II of clinical development for the prevention of acute rejection after solid organ transplantation and psoriasis, but this reseach had being discontinued.