Cilengitide is a cyclized Arg-Gly-Glu (RGD)-containing pentapeptide that selectively blocks activation of the αvβ3 and αvβ5 integrins. Its precursor was first synthesized in 1995 as c(RGDfV), and later modified by the incorporation of N-methyl Val c(RGDfMetV), generating the current form of the drug. Cilengitide displays subnanomolar antagonistic activity for αvβ3 and αvβ5, and is the first integrin antagonist evaluated in clinical phase I and II trials for treatment of glioblastoma and several other tumor types. Cilengitide-induced glioma cell death and inhibition of blood vessel formation may use different molecular mechanisms, including regulation of tumor hypoxia and activation of apoptotic pathways. Cilengitide inhibits cell signaling through FAK-Src-Akt and Erk mediated pathways in endothelial and tumor cells and attenuates the effect of VEGF stimulation on growth factor signaling. Cilengitide has shown encouraging activity in patients with glioblastoma as single agent, and in association with standard RT and temozolomide.

Amelubant, its metabolite BIIL 260 (formed by removal of the ethoxycarbonyl protecting group), and its major metabolite BIIL 315 (formed by removal of the protecting group and glucuronidation) had potent in vitro and in vivo Leukotriene B4 receptor antagonistic properties. Amelubant has been in phase II clinical trials by Boehringer Ingelheim for the treatment of cystic fibrosis, chronic obstructive pulmonay disease, bronchial asthma and rheumatoid arthritis. However, this research has been discontinued. In 2002, orphan drug designation was received in E.U. for the treatment of cystic fibrosis. Serious adverse events of Amelubant were characterized by increased presentation of respiratory signs and/or symptoms associated with pulmonary exacerbation and resulted in admission to a hospital and/or administration of IV antibiotics.

Palifosfamide or ZIO-201 (isophosphoramide mustard; IPM), a bi-functional DNA alkylator, is the active metabolite of ifosfamide (IFOS). IFOS and the related drug cyclophosphamide (CPA) are widely used anti-cancer drugs. Both are pro-drugs and need to be metabolized to be active. Their clinical use is limited by the toxicity associated with some of their metabolites. Palifosfamide has shown efficacy in diverse cancer models. ZIOPHARM Oncology Inc, under license from Dekk-Tec Inc, was developing palifosfamide, a formulation of isophosphoramide mustard with tris(hydroxymethyl)aminomethane salt-stabilization (palifosfamide-tris) and previously with lysine-stabilization (palifosfamide-lys). Preclinical studies and phase I and I/II clinical trials demonstrated that palifosfamide-tris had an antitumor efficiency comparable or superior to that of ifosfamide. To date ZIO-201 is not present in ZIOPHARM pipeline.

Alvocidib (also known as Flavopiridol or HMR-1275) is a flavonoid alkaloid CDK9 kinase inhibitor under clinical development for the treatment of acute myeloid leukemia, by Tolero Pharmaceuticals, Inc. As a broad spectrum CDK inhibitor, Alvocidib can inhibit cell cycle progression in either G1 or G2 and induces G1 arrest in either MCF-7 or MDA-MB-468 cells by inhibition of the CDK4 or CDK2 kinase activity. Alvocidib exhibits potent cytotoxicity against a wide variety of tumor cell lines (LNCAP, HCT116, A2780, K562, PC3, and Mia PaCa-2) with IC50 values ranging from 16 nM for LNCAP to 130 nM for K562. Administration of Alvocidib at 7.5 mg/kg for 7 days displays slight antitumor activity against P388 murine leukemia, and active against the human A2780 ovarian carcinoma implanted sc in nude mice). Alvocidib treatment at 1-2.5 mg/kg for 10 days significantly suppresses collagen-induced arthritis in mice in a dose-dependent manner, by inhibiting synovial hyperplasia and joint destruction, whereas serum concentrations of anti-collagen type II (CII) Abs and proliferative responses to CII are maintained. Tolero Pharmaceuticals Inc. announced that the FDA has granted orphan drug designation for Alvocidib, its cyclin-dependent kinase small molecule inhibitor, for the treatment of patients with acute myeloid leukemia.

SER-100 (previously known as ZP120, Ac-RYYRWKKKKKKK-NH2) is a peripherally acting orphanin FQ/nociceptin (ORL-1) receptor agonist that is in development with Serodus Pharmaceuticals for the treatment of Isolated systolic hypertension. SER-100 is a peripherally acting, highly potent and selective NOP receptor partial agonist, which was developed by coupling a chain of six lysine residues to an existing NOP receptor partial agonist hexapeptide, Ac-RYYRWK-NH2 to improve meta-bolic stability. SER-100 has sodium-potassium-sparing aquaretic and anti-natriuretic activity. SER-100 exerts a chronic hypotensive and bradycardic effects in rodents, including models of systemic and pulmonary hypertension. SER-100 produces its cardiovascular effects, at least in part, by inhibition of cardiac and vascular sympathetic activity. In terms of clinical evaluation, SER-100 was originally assessed in a randomized, double-blind, placebo controlled Phase II trial as add-on therapy in patients with sub-acute decompensated chronic heart failure (NCT00283361); how-ever, the clinical development of the peptide for this indication was terminated prematurely due to significant hypotensive activity, primarily on systolic blood pressure (SBP). Nonetheless, as a result of this profound drop in SBP, SER-100 (10 mg, s.c., bid) was investigated in a randomized, placebo-controlled study in patients with treatment-resistant isolated systolic hypertension (NCT01987284) and found to produce a meaningful and long lasting drop in SBP(~7 mmHg) and diastolic (~4 mmHg) blood pressure (DBP),as well as being safe and well-tolerated. FDA has granted an Orphan Drug Designation for SER-100 in pulmonary arterial hypertension (PAH).

GO-203-2c is a cell-penetrating peptide that binds to MUC1, a protein that causes cancer (oncoprotein). MUC1 is over-expressed in many human cancers, such breast, prostate, lung, colon, pancreas, and ovary cancer, and has been associated with poor prognosis. GO-203-2c blocks homodimerization of the MUC1-C subunit required for nuclear translocation and downstream signaling. This binding eventually leads to cell death (in laboratory setting). Since MUC1 is over-expressed in many cancers, the potential of GO-203-2c in treatment of cancers is being investigated. A phase I clinical trial has been completed in which GO-203-2c was shown to be safe and demonstrating both anti-leukemia and immunomodulatory effects. A phase II study is investigating its potential in the treatment of Acute Myeloid Leukemia.