Zosuquidar (LY-335979) is an experimental antineoplastic drug. It is is a potent modulator of P-glycoprotein-mediated multi-drug resistance with Ki of 60 nM. Zosuqidar was initially characterized by Syntex Corporation, which was acquired by Roche in 1990. Roche licensed the drug to Eli Lilly in 1997. It was granted orphan drug status by the FDA in 2006 for AML. Zosuquidar Trihydrochloride had been in phase III clinical trials by Kanisa Pharmaceuticals for the treatment of acute myeloid leukaemia. However, this research has been discontinued.

CPI-613 is a lipoate derivative synthesized to be catalytically inert but to potentially mimic lipoate catalytic intermediates. The drug is in phase II of clinical trials for the treatment of Myelodysplastic syndromes; Pancreatic cancer; Small cell lung cancer; Solid tumors; Bile duct cancer; Acute Myeloid leukemia. The mechanism of CPI-613 action can be explained by (I) inhibition of tumor cell pyruvate dehydrogenase complex (PDC) through activation of pyruvate dehydrogenase kinases leading to inactivating phosphorylation of the E1alpha-subunit of PDC; and (II) inhibition of alpha-ketoglutarate dehydrogenase.

2-Cyano-3,12-dioxooleana-1,9-diene-28-oic acid (CDDO, also known as Bardoxolone) is a synthetic triterpenoid that displays potent anti-inflammatory and antitumorigenic activities. CDDO was in the clinical trial phase I for the treatment patients with Solid tumors and leukemia, but that studies were discontinued. It is known, that CDDO blocks the cellular synthesis of inducible nitric oxide synthase and inducible COX-2. In addition, was discovered, that CDDO disrupted intracellular redox balance and thereby induce apoptosis. Moreover, CDDO is a ligand for peroxisome proliferator-activated receptor that it induces genes regulated by Nrf2, including heme oxygenase-1 and eotaxin-1, which play a role in antioxidant response element signaling activity.

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.

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).

AR-42, also known as (S)-HDAC-42, is a phenylbutyrate-based histone deacetylase (HDAC) inhibitor. HDACs are enzymes that determine acetylation status of histones, thereby affecting chromatin structure and regulating the expression and activity of numerous proteins involved in both cancer initiation and cancer progression. AR-42 possesses antitumor activity at multiple cellular levels. It is currently in Phase I/Ib trials for hematological malignancies and solid tumors.

BI-2536, an inhibitor of Polo-like kinase 1 (Plk-1) was being investigated by Boehringer Ingelheim as a possible treatment for cancer. BI-2536 inhibits Plk1 enzyme activity at low nanomolar concentrations. The compound potently causes a mitotic arrest and induces apoptosis in human cancer cell lines of diverse tissue origin and oncogenome signature. BI-2536 inhibits growth of human tumor xenografts in nude mice and induces regression of large tumors with well-tolerated intravenous dose regimens. In treated tumors, cells arrest in prometaphase, accumulate phosphohistone H3, and contain aberrant mitotic spindles. This mitotic arrest is followed by a surge in apoptosis, detectable by immunohistochemistry and noninvasive optical and magnetic resonance imaging. For addressing the therapeutic potential of Plk1 inhibition, BI-2536 has progressed into clinical studies in patients with locally advanced or metastatic cancers. It underwent phase II clinical studies for the treatment of breast cancer; non-small cell lung cancer; pancreatic cancer; prostate cancer; small cell lung cancer, but these studies were discontinued later.

Phorbol 12-myristate 13-acetate (PMA) also commonly known as 12-O-Tetradecanoylphorbol-13-acetate (TPA) is a phorbol ester that is commonly used to activate phospholipid-dependent protein kinase (protein kinase C). PMA/ TPA possesses potential antineoplastic effects and was studied in phase II clinical trials together with dexamethasone in patients with relapsed or refractory acute myeloid leukemia. In addition, PMA/ TPA participated in phase I trial for treating patients with hematologic cancer or bone marrow disorder that has not responded to previous treatment. Nevertheless, both clinical trials were terminated. Besides, PMA/ TPA was studied in patients with solid tumors, which had depressed white blood cell and neutrophil counts because of prior treatment with cytotoxic cancer chemotherapeutic drugs. It was shown, that the drug increased the low white blood cell and neutrophil counts toward the normal range.

JNJ-28312141 is an orally active colony-stimulating factor-1 receptor and FMS-related receptor tyrosine kinase-3 inhibitor. In preclinical models, JNJ-28312141 caused regression of ITD-FLT3–dependent MV-4-11 AML xenografts. The drug also suppressed the growth of H460 non-small cell lung adenocarcinoma xenografts and inhibited osteoclastogenesis and osteolysis in a rat model of metastatic bone disease.

The compound StemRegenin 1 (SR1) is a selective, cell-permeable, small molecule that promotes the self-renewal of human hematopoietic stem cells in culture. SR1 is an antagonist of the aryl hydrocarbon receptor. SR1 is the first small molecule that promotes robust expansion/self-renewal of human CD34 peripheral blood and cord blood hematopoietic stem cells (HSCs). The culture of HSCs with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. SR1 can be potentially used for ex vivo expansion of normal HSCs or leukemic stem/progenitor cells