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.

L-778123 is a dual inhibitor of Farnesyl Protein Transferase (FPTase) and Geranylgeranyl Protein Transferase type-I (GGPTase-I), which can completely inhibit Ki-Ras prenylation. L-778123 has been used in phase I clinical trials to determine its effectiveness in treating patients with recurrent or refractory solid tumors. L-778123 was also studied in combination with paclitaxel to determine efficacy as a treatment for both recurrent or refractory solid tumors, and lymphomas.

GSK-2256294 is a potent, reversible, tight binding inhibitor of isolated recombinant human sEH (soluble epoxide hydrolase) (IC50 = 27 pM; t1/2 = 121 min) and displays potent inhibition against the rat (IC50 = 61 pM) and murine (IC50 = 189 pM) orthologs of sEH. GSK-2256294A also displays potent cellular inhibition (IC50 = 0.66 nM) of sEH in an assay developed using a cell line transfected with the human sEH enzyme. GSK-2256294 was well-tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD. GSK-2256294 is in phase I clinical trials for the treatment of COPD.

HSP-990 is an oral Hsp90 inhibitor being developed by Novartis in a collaboration with Vernalis. It is also known by NVP-HSP990. HSP-990 is an inhibitor of human heat-shock protein 90 (Hsp90) with potential antineoplastic activity. Hsp-990 binds to and inhibits the activity of Hsp90, which may result in the proteasomal degradation of oncogenic client proteins, including HER2/ERBB2, and the inhibition of tumor cell proliferation. Hsp90, upregulated in a variety of tumor cells, is a molecular chaperone that plays a key role in the conformational maturation, stability and function of oncogenic signaling proteins, such as HER2/ERBB2, AKT, RAF1, BCR-ABL, and mutated p53, as well as many other molecules that are important in cell cycle regulation and/or immune responses.

Donitriptan hydrochloride (F 11356) was developed by Pierre Fabre as a brain penetrant 5-HT1B/1D agonist. Which inhibits capsaicin-induced external carotid vasodilation and produces selective carotid vasoconstriction in various animal species. In January 2001, donitriptan had completed phase I trials for migraine and was scheduled to enter phase II development, but before development in phase II, this drug was discontinued.

GLPG-0492, an orally available selective androgen receptor modulator (SARM) was tested in a Phase I Proof of Mechanism study to assess the effect on muscle function in healthy volunteers. A biomarker effect similar to that of Oxandrolone was observed, but the data were insufficient for Galapagos to pursue GLPG-0492 further in cachexia, and further development of the compound was discontinued. GLPG-0492 is currently under development for musculo-skeletal diseases such as sarcopenia and Duchenne muscular dystrophy.

Juvantia Pharma and Orion developed ORM-12741, also known as ORM-10921, a novel selective antagonist of alpha-2C adrenoceptors for the treatment of depression and Alzheimer's disease. ORM-12741 participated in phase II clinical trial where was evaluated the safety and efficacy of the drug in patients with Alzheimer's disease. In spite of the successfully completed phase II, further study of the drug for this disease was discontinued. In addition, ORM-12741 participated in clinical trial phase II to prove the concept that this drug could prevent blood vessel spasms for Raynaud's phenomenon. Raynaud's phenomenon is a disorder of the digital blood vessels resulting in episodic impairment of blood flow. However, this study was terminated because of the recommendation by study Data and Safety Monitoring Committee to the sponsor following the interim analysis of 8 subjects.

CPI-0610 is a small molecule inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, with potential antineoplastic activity. Upon administration, the BET inhibitor CPI-0610 binds to the acetylated lysine recognition motifs on the bromodomain of BET proteins, thereby preventing the interaction between the BET proteins and acetylated histone peptides. This disrupts chromatin remodeling and gene expression. Prevention of the expression of certain growth-promoting genes may lead to an inhibition of tumor cell growth. CPI-0610 is currently being evaluated in three Phase 1 clinical trials in the U.S.

GS-9820 (formerly CAL-120) is an oral, small molecule delta selective Phosphatidylinositol 3-kinases (PI3 kinase) inhibitor, a first in class compound, with greater than 200-fold selectivity in cell-based assays for the delta isoform as compared to other class isoforms. GS-9820 is designed to induce cancer cell death and inhibit signaling pathways associated with cancer cell dependence on the tumor microenvironment. GS-9820 is on the phase I of clinical trial, where has to be determined the appropriate dosing regimen of drug in subjects with lymphoid malignancies.

Omipalisib, also known as GSK2126458, is a small-molecule pyridylsulfonamide inhibitor of phosphatidylinositol 3-kinase (PI3K) with potential antineoplastic activity. Omipalisib (GSK2126458, GSK458) is a highly selective and potent inhibitor of p110α/β/δ/γ, mTORC1/2 with Ki of 0.019 nM/0.13 nM/0.024 nM/0.06 nM and 0.18 nM/0.3 nM in cell-free assays, respectively. It is also a low picomolar inhibitor of the common activating mutants of p110a (E542K, E545K, and H1047R) found in human cancer. Omipalisib (GSK2126458) binds to and inhibits PI3K in the PI3K/mTOR signaling pathway, which may trigger the translocation of cytosolic Bax to the mitochondrial outer membrane, increasing mitochondrial membrane permeability and inducing apoptotic cell death. Bax is a member of the proapoptotic Bcl2 family of proteins. PI3K, often overexpressed in cancer cells, plays a crucial role in tumor cell regulation and survival. GlaxoSmithKline (GSK) is developing omipalisib, a phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor as well as mTOR complex 1 and 2 inhibitor, for the potential oral treatment of cancer and idiopathic pulmonary fibrosis.