Defactinib is an oral, investigational drug candidate for the treatment of various solid tumors. Through dual inhibition of FAK and PYK2, defactinib targets key resistance mechanisms in the tumor microenvironment (TME), including limited local immune response, dense stroma, and resident cancer stem cells, that may limit the effectiveness of current and investigational treatments. Treatment-related adverse events are: unconjugated hyperbilirubinemia, fatigue and headache.

LY-3009120 is an orally available inhibitor of all members of the serine/threonine protein kinase Raf family, including A-Raf, B-Raf, and C-Raf protein kinases, with potential antineoplastic activity. Upon administration, pan-RAF kinase inhibitor LY3009120 inhibits Raf-mediated signal transduction pathways, which may inhibit tumor cell growth. Raf protein kinases play a key role in the RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, which is often dysregulated in human cancers and plays a key role in tumor cell proliferation and survival. LY3009120 is being investigated in phase I clinical trial.

Daidzein, an isoflavonoid phytoestrogenic compound found in soybeans, possesses various biological properties. It may induce apoptosis of choriocarcinoma cells in a dose-dependent manner via the mitochondrial apoptotic pathway, in addition, it promotes proliferation and differentiation in osteoblastic OCT1 cells via activation of the BMP-2/Smads pathway. Daidzein exerts neuroprotective effects through the novel extranuclear GPR30 and the classical transcriptionally acting ERβ.

Pevonedistat (MLN4924), discovered by Millennium, is a small molecule inhibitor of the NEDD8-Activating Enzyme (NAE), a key component of the protein homeostasis pathway. MLN4924 is a mechanism-based inhibitor of NAE and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme. The NEDD8-MLN4924 adduct resembles NEDD8 adenylate, the first intermediate in the NAE reaction cycle, but cannot be further utilized in subsequent intraenzyme reactions. The stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by MLN4924. This drug is in phase II clinical trial for the treatment acute myeloid leukemia, chronic myelomonocytic leukemia and myelodysplastic syndromes. In addition in phase I for treatment acute lymphoblastic leukemia. The ability of MLN4924 to cross the blood-brain barrier, its low toxicity, and clinical efficacy in other cancers suggests that this drug is an attractive treatment against glioblastomas.

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.

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.

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.

Trichostatin A (TSA) was originally isolated as an antifungal antibiotic along with its fermentation congeners trichostatin B ((TSA)3-Fe) and the D-glucopyranosides trichostatin C and D. TSA inhibits HDAC in the low nanomolar range and is an inducer of histone hyperacetylation, both in vitro and in vivo. It inhibits all class I and II deacetylases to a similar extent in both tumor and non-tumor cells, although HDAC4 is slightly resistant when compared with HDAC1 and HDAC6. Class III HDAC is not affected by TSA. It has been shown that TSA dosedependently inhibits growth and induces apoptosis in a plethora of carcinoma cell lines in vitro. Recently, it was also found that TSA inhibits angiogenesis, which is important for the growth and metastasis of solid tumors, both in vivo and in vitro. In HT-29 colon carcinoma cells, a single dose of TSA induced transient hyperacetylation of histone H4 resulting in the induction of p21WAF1/Cip1 and inhibition of cellular proliferation at both the G1 and G2 phases of the cell cycle. Growth inhibition was associated with decreased cyclin D1 mRNA and cdk6 protein levels and increased cyclin D3 protein and p21WAF1/Cip1 mRNA levels. Cyclin D1 protein, cyclin D3 mRNA, cdk2 and cdk4 remained unaffected. In addition, TSA induced apoptosis by upregulating the expression of the pro-apoptotic genes ID1, ID2 and ID3, whereas the expression of the anti-apoptotic genes BclxL and Hsp27 was decreased In vivo, TSA induces differentiation and shows chemotherapeutic activity against N-methylnitrosureainduced rat mammary cancer without toxic side effects. TSA may also have therapeutic potential for the treatment of a variety of genetic and infectious diseases since silenced, transduced genes are reactivated probably due to structural changes of the chromatin on integrated viral sequences.

Cenisertib (also known as R763) is water-soluble, synthetic small molecule aurora kinase inhibitor with potential antineoplastic activity. Cenisertib is a potent adenine triphosphate-competitive inhibitor of Aurora kinase isoforms A–C, disrupting mitotic spindle activity, blocking cell separation, and leading to polyploidy and cell death. At low nanomolar concentrations, Cenisertib also inhibits other kinases involved in cell survival and proliferation including FLT3, BCR-ABL1, and BCR-ABL1 with T315I mutation. It also inhibits JAK2 kinase, but at higher concentrations. Preclinically, Cenisertib has demonstrated potent antitumor activity as a single agent and in combination treatment in leukemia cell lines, freshly isolated leukemia cells, and leukemia xenograft models. Toxicities appear to be related mainly to the gastrointestinal and hematopoietic systems. In animal models, activity and toxicity depend not only on dose but also on the schedule of administration.

Orteronel (TAK-700) is a non-steroidal antiandrogen, discovered by Takeda Pharmaceutical Company Limited, that selectively inhibits the 17,20 lyase enzyme (CYP17A1). This enzyme, which is present in both the testes and adrenal glands, is central to the production of steroidal androgens. Synthesis of androgens outside the testes contributes to disease progression in castration-resistant prostate cancer (CRPC). In phase III of clinical trials for metastatic, hormone-refractory prostate cancer it wasn’t shown overall survival rates, and development was voluntarily terminated as a result.