Sepantronium bromide (YM155) is a selective survivin suppressant that exhibits potent antitumor activities by inducing apoptosis and autophagy in various types of cancer. Sepantronium bromide inhibited the growth of various human cancer cell lines in vitro with GI50 values in the low nM range. Sepantronium bromide blocked the growth of 119 human cancer cell lines, with the greatest inhibition in lines derived from non-Hodgkin's lymphoma, hormone-refractory prostate cancer, ovarian cancer, sarcoma, non-small-cell lung cancer, breast cancer, leukemia, and melanoma, with an average GI50 of 15 nM. Sepantronium bromide inhibited the growth of tumor cell lines regardless of their p53 status and demonstrated significant antitumor activity in 5 mice xenograft models. It also caused tumor regressions in vivo, possibly by its effects in reducing intratumoral survivin expression levels and increasing apoptosis. Sepantronium Bromide had been in phase II clinical trials by Astellas for the treatment of prostate cancer, melanoma, non-Hodgkin's lymphoma, breast cancer, diffuse large B cell lymphoma, non-small cell lung cancer (NSCLC) and other solid tumors. This compound had also been in clinical trials by National Cancer Institute (NCI) for the treatment of solid tumors (phase I) and advanced non-small cell lung cancer (NSCLC) (phase II). However, all these researches about this compound for all indications were discontinued.

Rubitecan [Orathecin™] is a topoisomerase I inhibitor extracted from the bark and leaves of the Camptotheca acuminata tree, which is native to China. Rubitecan is an oral compound being developed for the treatment of pancreatic cancer and other solid tumours by SuperGen. Rubitecan binds to and inhibits the enzyme topoisomerase I and induces protein-linked DNA single-strand breaks, thereby blocking DNA and RNA synthesis in dividing cells; this agent also prevents repair of reversible single-strand DNA breaks.

Indoximod is an orally available Indoleamine 2,3-dioxigenase inhibitor. It shows higher potency in reversing IDO-mediated T cell suppression. Indoximod improves the efficacy of multiple chemotherapeutics agents and some immunological checkpoints mediators in Phase I/II clinical studies for metastatic breast cancer, metastatic melanoma, non-small cell lung cancer, primary malignant brain tumors, metastatic pancreatic cancer, as well as metastatic prostate cancer.

Pictilisib is an oral potent inhibitor of class I PI3K with nanomolar activities against p110alpha, p110beta, p110delta, and p110gamma. The drug was developed for the treatment of solid tumors and reached phase II in patients with breast cancer and lung carcinoma, however its development was terminated.

APTO-253 is a novel small molecule that can induce expression of the genes that code for the Krüppel-like factor 4 (KLF4) master transcription factor and for the p21 cell cycle inhibitor protein, and can inhibit expression of the c-Myc oncogene, leading to cell cycle arrest and programmed cell death (apoptosis) in human-derived solid tumor and hematologic cancer cells. A Phase 1 study with APTO-253 was completed and demonstrated modest clinical activity in patients with colon cancer, acute leukemia, myelodysplastic syndrome, hematological malignancies and non-small cell lung cancers.

Pfizer's CP-547632 is a selective inhibitor of VEGFR-2 tyrosine kinase that was discovered during Pfizer's collaboration with OSI Pharmaceuticals. CP-547632, was identified as a potent inhibitor of the VEGFR-2 and basic fibroblast growth factor (FGF) kinases (IC(50) = 11 and 9 nM, respectively). It is selective relative to epidermal growth factor receptor, platelet-derived growth factor beta, and other related TKs. It also inhibits VEGF-stimulated autophosphorylation of VEGFR-2 in a whole cell assay with an IC(50) value of 6 nM. After oral administration of CP-547632 to mice bearing NIH3T3/H-ras tumors, VEGFR-2 phosphorylation in tumors was inhibited in a dose-dependent fashion (EC(50) = 590 ng/ml). CP-547,632 is a well-tolerated, orally-bioavailable inhibitor presently under clinical investigation for the treatment of human malignancies. CP-547632 is in phase I for the treatment of diabetic retinopathy and age-related macular degeneration.

AZD-3759 is an oral inhibitor of both wild-type and mutant EGFR with IC50 values in nanomolar range. The drug was discovered by AstraZeneca for the treatment of non-small-cell lung cancer with CNS metastases. AZD-3759 can penetrate the blood-brain barrier and was confirmed to be effective in vitro with NSCLC cell lines as well as in mouse model of brain metastases. AZD-3759 is currently in Phase 1 clinical trial.

Prinomastat is a synthetic hydroxamic acid derivative with potential antineoplastic activity. Prinomastat inhibits matrix metalloproteinases (MMPs) (specifically, MMP-2, 9, 13, and 14), thereby inducing extracellular matrix degradation, and inhibiting angiogenesis, tumor growth and invasion, and metastasis. As a lipophilic agent, prinomastat crosses the blood-brain barrier. Pfizer conducted multicenter, randomized, double-bind, placebo-controlled trials to evaluate the safety and efficacy of prinomastat in combination with standard chemotherapy in patients with advanced hormone refractory prostate cancer and non-small cell lung cancer. However, this study has been terminated for the reason that Prinomastat did not improve the outcome of chemotherapy in non-small cell Lung cancer patients.

Sitravatinib (MGCD516) is a receptor tyrosine kinases (RTK) inhibitor that blocks a wide array of RTKs known to be amplified/overexpressed in sarcomas, which are key regulators of signaling pathways that lead to cell growth, survival and tumor progression. It is involved in driving sarcoma cell growth with IC50 of 3980 nM and is superior to other multi-kinase inhibitors in inhibiting cell proliferation, RTK phosphorylation, and phosphorylation of downstream effectors. The efficacy of sitravatinib was tested using a wide panel of sarcoma cell lines, including malignant peripheral nerve sheath tumor (MPNST), Ewing sarcoma (A673), osteosarcoma (Saos2), and liposarcoma (DDLS, LS141). Both in vitro and in vivo efficacy sitravatinib was significantly better that the other two multi-kinase inhibitors, imatinib and crizotinib. Sitravatinib treatment not only inhibits tumor cell proliferation at low nanomolar concentrations in vitro but also results significant tumor growth suppression in vivo in mouse xenograft models. Sitravatinib is being evaluated in a Phase 1b dose expansion cohort in selected patients with specific genetic alterations that are drivers of tumor growth, with an initial focus on Non-Small-Cell Lung carcinoma (NSCLC) and in other solid tumors where sitravatinib may confer a benefit. Its efficacy and safety is also being tested in Phase II clinical trials in patients with advanced liposarcoma as a monotherapy and NSCLC in combination with nivolumab.

Dofequidar (MS-209), a quinolone-derived sphingomyelin synthase inhibitor that blocks P-glycoprotein and multidrug resistance-associated protein-1, is under development by Schering for the potential treatment of multidrug resistant tumors. MS-209 had been in phase III clinical trials for the treatment of breast cancer and non-small lung cancer. But this research was discontinued in 2004. Detected adverse events are: nausea, vomiting, leukopenia, neutropenia, anorexia, constipation.