Entinostat (MS-275) is an orally active, highly selective, small-molecule histone deacetylase inhibitor (HDACi) derived from benzamide. Entinostat preferentially inhibited HDAC1 versus HDAC3 and had no inhibitory activity toward HDAC8. The time to maximum plasma concentration (tmax) of entinostat ranged from 0.5 to 60h (median of 2h). Elimination of the drug was bi-exponential, with a terminal half-life of 30-80h. Entinostat is a well-tolerated that demonstrates promising therapeutic potential in both solid and hematologic malignancies. Its efficacy does not appear directly dose-related, and as such, more relevant biomarkers are needed to adequately assess its activity.

Resiquimod is an imidazoquinolinamine and Toll-like receptor (TLR) agonist with potential immune response modifying activity. Resiquimod exerts its effect through the TLR signaling pathway by binding to and activating TLR7 and 8 mainly on dendritic cells, macrophages, and B-lymphocytes. This induces the nuclear translocation of the transcription activator NF-kB as well as activation of other transcription factors. This may lead to an increase in mRNA levels and subsequent production of cytokines, especially interferon-alpha (INF-a) and other cytokines, thereby enhancing T-helper 1 (Th1) immune responses. In addition, topical application of resiquimod appears to activate Langerhans' cells, leading to an enhanced activation of T-lymphocytes. Resiquimod is used as a topical gel[1] in the treatment of skin lesions[2] such as those caused by the herpes simplex virus[3][4] and cutaneous T cell lymphoma. Due to its immunostimulatory activity, this agent may potentially be used as a vaccine adjuvant.

Odiparcil is a novel, orally active beta-d-thioxyloside analog with antithrombotic activity associated with a reduced risk of adverse bleeding events. Its unique mechanism of action is postulated by means of an elevation in circulating endogenous chondroitin sulfate-related glycosaminoglycans (GAGs) levels. Odiparcil has demonstrated good tolerability, safety and efficacy in phase I and phase IIa studies, in approximately 700 healthy volunteers and 1100 patients. The drug has been investigated in several preclinical models and its potential has been proven in MPS. It may be therefore anticipated that Odiparcil could prove beneficial to MPS patients (MPS I, II and VI) as a substrate reduction therapy as a stand-alone treatment on in adjunction to current treatments. U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to odiparcil (formerly known as IVA336) for the treatment of mucopolysaccharidosis VI (MPS VI), also known as Maroteaux-Lamy syndrome.

Darinaparsin is a novel mitochondrial-targeted agent being developed for the treatment of various hematologic and solid cancers. In a Phase II study in the US, intravenous darinaparsin demonstrated evidence of clinical activity in malignant lymphoma, and in particular peripheral T-cell lymphoma (PTCL). Darinaparsin was granted Orphan Drug Designation in the US and Europe as a treatment of PTCL. The oral formulation is also being tested in Phase I for the treatment of solid tumors. Darinaparsin induces G2/M cell cycle arrest and apoptosis in tumor cells, primarily through disruption of mitochondrial functions, increased reactive oxygen species (ROS) production and modulation of signal transduction pathways.

Tipifarnib is an oral farnesyltransferase (FTase) inhibitor which was developed by Janssen (J&J). Upon administration, tipifarnib inhibits FTase and thus suppresses the activity of downstream effectors. The drug reached phase III of clinical trials for such diseases as pancreatic cancer (terminated), colorectal cancer (terminated) and acute myeloid leukemia (in elderly patients).

Flindokalner (BMS 204352; MaxiPost™) is a neuroprotective agent with potential in the treatment of stroke developed by Bristol-Myers Squibb. Flindokalner is a potent and effective opener of two important subtypes of neuronal potassium channels, the calcium-activated, big-conductance potassium channels (K(Ca) channels) and voltage-dependent, non-inactivating potassium channels known as KCNQ channels. Flindokalner significantly reduced cortical infarct volume in a animal models of stroke. Flindokalner failed to show superior efficacy in acute stroke patients compared to placebo in a Phase III study.

Tumor hypoxia remains one of the greatest challenges in the treatment of solid tumors, as cancer cells in these regions are resistant to killing by radiation therapy and most anticancer drugs. Tirapazamine (3-Amino-1,2,4-benzotriazine-1,4-dioxide or SR 4233) is a cytotoxic drug with selective toxicity towards hypoxic mammalian cells. Under both aerobic and hypoxic conditions, tirapazamine is reduced by an intracellular reductase to form a highly reactive radical, which can cause DNA single- and double-strand breaks. In addition, tirapazamine under hypoxic conditions reduces the activity of topoisomerase II and stabilizes DNA topoisomerase II cleavable complexes, and these complexes remain bound to DNA. Despite the very promising results obtained in various preclinical studies and early-Phase clinical trials, several Phase III trials have failed to demonstrate any survival benefit of adding tirapazamine to chemotherapy or radiation therapy of cancers.

Forodesine hydrochloride is the salt of the synthetic high-affinity transition-state analog forodesine (BCX-1777, immucillin-H), a substrate designed to mimic the properties or the geometry of the transition state of reaction. It is an anticancer drug that has been developed for the treatment of different hematologic malignancies. In December 2006, orphan designation (EU/3/06/421) was granted by the European Commission to Napp Pharmaceuticals Research Limited, United Kingdom, for forodesine hydrochloride for the treatment of acute lymphoblastic leukemia. Forodesine hydrochloride has been evaluated in Phase I/Phase II clinical trials for several cancer types including chronic lymphocytic leukemia (CLL), B-Cell acute lymphoblastic leukemia and refractory cutaneous T-cell lymphoma (CTCL). Forodesine is a potent purine nucleoside phosphorylase (PNP) inhibitor that acts by elevating plasma 2'-deoxyguanosine (dGuo) and intracellular deoxyguanosine triphosphate, which in turn affects deoxynucleotide-triphosphate pools and induces cell death by apoptosis. Forodesine in the presence of dGuo inhibited the proliferation of CEM-SS (T-acute lymphoblastic leukemia) cells with an IC50 of 0.015 uM. This inhibition by forodesine and dGuo was accompanied by a 154-fold and 8-fold elevation of endogenous dGuo triphosphate (dGTP) and deoxyadenosine triphosphate (dATP) pools, respectively. Cytotoxic activity of forodesine in the presence of dGuo was selective to T lymphocytes. It is a 10- to 100-fold more potent inhibitor of human lymphocyte proliferation than other known PNP inhibitors such as PD141955 and BCX-34.8

Tesetaxel is a taxane derivative patented by Daiichi Pharmaceutical Co., Ltd. as antitumor agent. Preclinical research suggests that tesetaxel may overcome P-glycoprotein-mediated multidrug resistance, thereby facilitating extended intracellular retention and possibly clinical effectiveness. Tesetaxel exhibited potent cytotoxicity against various human and murine cancer cell lines and was particularly potent against cell lines expressing P-glycoprotein. Orally administered tesetaxel showed potent in vivo antitumor activity in murine syngeneic and human xenograft models. The cytotoxic effect of tesetaxel, unlike that of other taxanes, was not influenced by the level of P-glycoprotein expression or by the presence of a P-glycoprotein modulator. In patients with metastatic breast cancer, tesetaxel was shown to have significant, single-agent antitumor activity in two multicenter, Phase 2 studies.