Delanzomib (CEP-18770), a proteasome inhibitor, was being developed by Cepahlon (a subsidiary of Teva) for the treatment of cancer and immunological disorders. Delanzomib (CEP-18770) induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, Delanzomib (CEP-18770) has a strong antiangiogenic activity and potently represses RANKL-induced osteoclastogenesis. Delanzomib represses the proteasomal degradation of a variety of proteins, including inhibitory kappaBalpha (IkappaBalpha), resulting in the cytoplasmic sequestration of the transcription factor NF-kappaB; inhibition of NF-kappaB nuclear translocation and transcriptional up-regulation of a variety of cell growth-promoting factors; and apoptotic cell death in susceptible tumor cell populations. In vitro studies indicate that this agent exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells relative to the proteasome inhibitor bortezomib. Delanzomib has been in phase II clinical trials for the treatment of multiple myeloma (MM). However, this research has been discontinued. Currently Delanzomib is on Phase I clinical trial for Non-Hodgkin's lymphoma and Solid tumours.

BCX-4430 hydrochloride is a salt of an antiviral adenosine analog BCX4430 (Immucillin-A) that acts as a viral RNA-dependent RNA polymerase (RdRp) inhibitor. It was developed as a potential treatment for deadly filovirus infections such as Ebola virus disease and Marburg virus disease but also demonstrated broad-spectrum antiviral effectiveness against a range of other RNA virus families, including, bunyaviruses, arenaviruses, paramyxoviruses, and coronaviruses. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. BCX4430 inhibits infection of distinct filoviruses in human cells. Post-exposure administration of BCX4430 protects rodents against Ebola and Marburg virus disease and cynomolgus macaques from Marburg virus when administered as late as 48 hours after infection. BCX4430 is highly active in a Syrian golden hamster model of yellow fever, even when treatment is initiated at the peak of viral replication. BCX4430 also showed efficacy against Zika virus in a mouse model.

ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor. urora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases, which have been shown to play important roles in the pathology of several cancers. ENMD-2076 is tested in phase 2 clinical trials against ovarian cancer, breast cance, hepatocellular carcinoma and other malignancies.

Indolapril (CI-907) is a new orally active prodrug of nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor, developed by Warner-Lambert/Parke-Davis Pharmaceutical Research for treating hypertension. Indolapril is epimer of trandolapril, well-known ACE inhibitor currently in the market for hypertension treatment. Indolapril (Monoester form) and it’s active component (diacid form) produced concentration related ACE inhibition in guinea-pig serum (IC50 for monoester -- 0.1 mkM and for diacid -- 2.6 nM). In isolated rabbit aortic rings and in rat and dog autonomic studies, Indolapril is highly specific in suppressing the contractile or pressor responses to angiotensin I. In two-kidney, one-clip Goldblatt hypertensive rats, single daily doses (0.03-30 mg/kg p.o.) produced dose-dependent decreases in blood pressure; 3 mg/kg lowered blood pressure to normotensive levels. In the spontaneously hypertensive rat, subacute administration of Indolapril produced the same decrease in blood pressure as that obtained in the renal hypertensive rat. In diuretic-pretreated renal hypertensive dogs, 10 mg/kg normalized blood pressure. For equivalent drops in blood pressure, heart rate increases were less in Indolapril than in enalapril-treated renal hypertensive dogs. No side effects were observed with CI-907 in any of the conscious animals. The antihypertensive response to Indolapril (0.03-1.0 mg/kg p.o.) was found to correlate with inhibition of vascular tissue ACE, but not plasma or brain ACE in two-kidney, one-clip renal hypertensive rats.

Lupeol, a biologically active dietary triterpenoid, is found in many medicinal plants and different fruits such as olives, mangos, and strawberries. Lupeol exhibits a wide spectrum of pharmacological properties including anti-inflammatory, anti-cancer, anti-diabetic, anti-microbial, cardioprotective, and hepatoprotective activities. Lupeol inhibits LPS-induced microglial neuroinflammation via the P38-MAPK and JNK pathways and has therapeutic potential to treat various neuroinflammatory disorders. Lupeol possesses antiskin tumor-promoting effects in CD-1 mouse and inhibits conventional as well as novel biomarkers of tumor promotion. It strongly suppressed lipogenesis by modulating the IGF-1R/phosphatidylinositide 3 kinase (PI3K)/Akt/sterol response element-binding protein-1 (SREBP-1) signaling pathway in SEB-1 sebocytes, and reduced inflammation by suppressing the NF-κB pathway in SEB-1 sebocytes and HaCaT keratinocytes. Lupeol exhibited a marginal effect on cell viability and may have modulated dyskeratosis of the epidermis. These results demonstrate the clinical feasibility of applying lupeol for the treatment of acne.

Chlorothalonil (2,4,5,6-tetrachloroisophthalonitrile) is an organic compound mainly used as a broad spectrum, nonsystemic fungicide, with other uses as a wood protectant, pesticide, acaricide, and to control mold, mildew, bacteria, algae. Chlorothalonil reduces fungal intracellular glutathione molecules to alternate forms which cannot participate in essential enzymatic reactions, ultimately leading to cell death. Chlorothalonil is slightly toxic to mammals, but it can cause severe eye and skin irritation in certain formulations. Very high doses may cause a loss of muscle coordination, rapid breathing, nose bleeding, vomiting, and hyperactivity. Dermatitis, vaginal bleeding, bright yellow and/or bloody urine, and kidney tumors may also occur, followed by death. In a number of tests of varying lengths of time, rats which were fed a range of doses of chlorothalonil generally showed no effects on physical appearance, behavior, or survival. Kidney changes such as kidney enlargement were common. In the US, chlorothalonil is used predominantly on peanuts (about 34% of usage), potatoes (about 12%), and tomatoes (about 7%), though the EPA recognizes its use on many other crops. It is also used on golf courses and lawns (about 10%) and as a preservative additive in some paints (about 13%), resins, emulsions, and coatings. Chlorothalonil is commercially available in many different formulations and delivery methods. It is applied as a dust, dry or water-soluble grains, a wettable powder, a liquid spray, a fog, and a dip. It may be applied by hand, by ground sprayer, or by aircraft

ABC-294640 is an orally bioavailable and selective sphingosine kinase-2 (SphK2) inhibitor with IC50 of approximately 60 uM. ABC-294640 inhibits SK2, a lipid kinase that catalyzes formation of the lipid signaling molecule sphingosine 1-phosphate (S1P). S1P promotes cancer growth, and proliferation and pathological inflammation, including TNFα signaling and other inflammatory cytokine production. Specifically, by inhibiting the SK2 enzyme, ABC-294640 blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and are also involved in immune-modulation and suppression of innate immune responses from T cells. Preliminary evidence suggests that because of its specificity for targeting SK2, rather than SK1, ABC-294640 may have a better therapeutic ratio than nonspecific sphingosine kinase inhibitors or those targeting only SK1. Oral administration of ABC-294640 to mice bearing mammary adenocarcinoma xenografts results in dose-dependent antitumor activity associated with depletion of S1P levels in the tumors and progressive tumor cell apoptosis. Therefore, this newly developed SK2 inhibitor provides an orally available drug candidate for the treatment of cancer and other diseases. ABC-294640 has completed multiple successful pre-clinical studies in inflammatory, GI, radioprotection and oncology models, as well as a Phase I clinical study in cancer patients with advanced solid tumors.

Secoisolaricircsinol is one of the most abundant dietary lignans in various foods, such as plant seeds, whole grains, legumes, vegetables, and fruits. Secoisolariciresinol is the major lignin found in flaxseed and is present in a polymer that contains Secoisolariciresinol diglucoside. Secoisolariciresinol and Secoisolariciresinol diglucoside are known to have a number of health benefits, including reduction of the serum cholesterol levels, delaying of the onset of type 2 diabetes, and reduction of the formation of hormone-sensitive cancers such as breast, prostate, and colon cancers. Following the consumption of Secoisolariciresinol diglucoside, it is further converted by the bacteria in the colon of humans and other animals into aglycone Secoisolariciresinol and the mammalian lignans, enterodiol and enterolactone. The structures of enterodiol and enterolactone are similar to that of estradiol, an endogenous estrogen. This structural similarity accounts for the ability of these compounds to bind to estrogen receptors and to exert weak estrogenic or anti-estrogenic effects, depending on the presence of stronger estrogen. It is well known that Secoisolariciresinol has an estrogen-like activity and stimulates the cell growth of human breast cancer MCF-7 cells.

ZSTK474 is a new PI3K inhibitor with strong antitumor activity against human cancer xenografts without toxic effects in critical organs. Specifically, ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms. ZSTK474 blocks VEGF-induced cell migration and the tube formation in human umbilical vein endothelial cells (HUVECs), and inhibits the expression of HIF-1α and secretion of VEGF in RXF-631L cells, exhibiting potent in vitro antiangiogenic activity. ZSTK474 demonstrated prophylactic efficacy in a rat model of rheumatoid arthritis (RA) through inhibition of T cell and FLS functions.

Nivocasan (aka GS-9450) was discovered by LG Life Sciences and developed by Gilead Sciences. Nivocasan is an irreversible inhibitor of caspase 1, 8, and 9, and therefore able to prevent apoptosis. Nivocasan has been investigated as a treatment option for Hepatic fibrosis and Non-alcoholic steatohepatitis related to Hepatitis C infection. It had advanced to Phase II clinical trials before the development program was suspended.