Orantinib (SU-6668) is an orally bioavailable receptor tyrosine kinase inhibitor. Orantinib binds to and inhibits the autophosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), thereby inhibiting angiogenesis and cell proliferation. Orantinib also inhibits the phosphorylation of the stem cell factor receptor tyrosine kinase c-kit, often expressed in acute myelogenous leukemia cells. Orantinib was in phase II clinical trials for the treatment of breast cancer. It was also in phase III clinical trials for the treatment of hepatocellular carcinoma. However, this research was terminated in 2014. The compound was originally developed by Sugen (subsidiary of Pfizer). In 1998, a co-development agreement took place between Sugen and Taiho for the compound.

GSK-1482160 is being evaluated for treatment of inflammatory pain (such as arthritis). This compound acts on P2X7 receptors, expressed by cells of innate and adaptive immunity. P2X7 receptors are involved in the production of pro-inflammatory cytokines that are thought to be an important mediator of inflammation. By blocking P2X7 receptors, less inflammatory chemicals are released, which possibly results in less inflammatory pain. Because of its ability to target P2X7R with high selectivity and to be radiolabelled with 11C, GSK-1482160 was suggested to be a useful biomarker for neuroinflammation via positron emission tomography (PET).

GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma. EZH2 inactivation by GSK126 is also effective in killing MM cells and CSCs as a single agent or in combination with bortezomib. Clinical trial of GSK126 in patients with MM may be warranted. GSK126 is undergoing phase I trials for hypermethylation-related cancers. GSK126 is in phase I diffuse large B cell lymphoma and follicular lymphoma. GSK126 inhibits cell migration and angiogenesis in solid tumor cell lines through down-regulation of VEGF-A expression. Thus, it may be considered as a novel anticancer drug candidate for solid tumor.

MK-3281 is a potent and orally bioavailable inhibitor of HCV NS5B polymerase which combined excellent cell-based potency with good pharmacokinetic properties in preclinical species. MK-3281 was efficacious in the chimeric mouse model of HCV infection.

Nitroarginine (LNNA), an analog of L-arginine, is a competitive inhibitor of nitric oxide synthase which has been shown to prevent glutamate toxicity. Nitroarginine has been experimentally tested for its ability to prevent ammonia toxicity and ammonia-induced alterations in brain energy and ammonia metabolites. The Kd value (k(off)/k(on)) of bovine brain cNOS for LNNA was 15 nM. In contrast to the potent and slow onset of LNNA inhibition of brain cNOS, LNNA inhibition of inducible mouse macrophage NOS (iNOS) was weaker (Ki = 4.4 uM) and rapidly reversible. Thus, LNNA was a 300-fold more potent inhibitor of bovine brain cNOS than mouse macrophage iNOS. By inhibiting nitric oxide synthase LNNA causes the selective reduction of blood flow to tumor cells. Despite the potential of LNNA to function as an adjuvant in cancer therapies, its poor solubility and stability have hindered the development of an injectable formulation of LNNA that is suitable for human administration.

Pinometostat, also known as EPZ-5676, is a small molecule inhibitor of histone methyltransferase with potential antineoplastic activity. Upon intravenous administration, EPZ-5676 specifically blocks the activity of the histone lysine-methyltransferase DOT1L, thereby inhibiting the methylation of nucleosomal histone H3 on lysine 79 (H3K79) that is bound to the mixed lineage leukemia (MLL) fusion protein which targets genes and blocks the expression of leukemogenic genes. Epizyme is developing pinometostat, a small molecule inhibitor of DOT1L, for the treatment of patients with MLL-r, a genetically defined acute leukemia. Epizyme is conducting a phase 1 clinical trial in pediatric patients. Epizyme is evaluating preclinical combinations of pinometostat with other anti-cancer agents in MLL-r leukemia. Pinometostat is being developed in collaboration with Celgene. Epizyme retains all U.S. rights to pinometostat and has granted Celgene an exclusive license to pinometostat outside of the U.S.