KYORIN Pharmaceutical has developed a new sphingosine 1-phosphate (S1P) receptor type 1 agonist, 2-amino-2-propanediol hydrochloride (KRP-203), for immunomodulation in autoimmune diseases and organ transplantation. This drug was in phase II clinical trial for the treatment Ulcerative Colitis, but this study was terminated. In addition, it has been investigated for the treatment of Cutaneous Lupus Erythematosus and Crohn's Disease, these phases II clinical trial studies were successfully completed.

Amgen is developing AMG-900, an orally active, small molecule aurora kinase A, B and C inhibitor for the treatment of solid tumours and haematological malignancies. In tumor cells, AMG-900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG-900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG-900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG-900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG-900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG-900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG-900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.

Esuberaprost (314d) is an active enantiomer of beraprost, a prostacyclin analog. The pharmacologic action of esuberaprost is mediated by specifically binding to PGI2 receptors in smooth muscle cells (the blood vessel’s endothelium) and platelets. Upon binding, the compound widened blood vessels, preventing the formation of blood clots, and lowering blood pressure in the lungs. As a result, it was expected to improve the symptoms of pulmonary arterial hypertension. United Therapeutics announced it has ended its Phase 3 BEAT trial testing esuberaprost as an add-on therapy to its product Tyvaso (inhaled treprostinil) for clinically symptomatic patients with pulmonary arterial hypertension (PAH). According to a company press release, the study failed to reach its main endpoint of delaying the time to first clinical worsening events.

Recilisib (also known as EX-RAD or ON-01210) is a radioprotectant, which means that this compound can protect cells from harmful effects of ionizing radiation. Unlike other radioprotectors, recilisib is not a free-radical scavenger or responsible for cell cycle arrest. Recilisib was suggested to have a different radiation protection mechanism involving DNA repair pathways. This compound has been studied as prophylactic (use prior to radiation exposure) and therapeutic (after exposure to radiation) drug. In studies with healthy volunteers, recilisib was rapidly absorbed and well-tolerated, with only mild adverse events. Phase I clinical trials have been completed.

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.

5-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile monofumarate (PRX-08066) is a selective 5-hydroxytryptamine receptor 2B (5-HT2BR) antagonist that causes selective vasodilation of pulmonary arteries. This drug was discovered and developed by Predix (later Epix) Pharmaceuticals and is being researched for the treatment of pulmonary arterial hypertension. In animal studies, PRX-08066 has been found to reduce several key indicators of pulmonary arterial hypertension and improved cardiac output, with similar efficacy to established drugs for this condition such as bosentan, sildenafil, beraprost and iloprost.

Nevanimibe (also known as PD-132301 and ATR101) is an acetyl-CoA C-acyltransferase (ACAT1) inhibitor. Millendo Therapeutics is currently advancing the development of nevanimibe for the treatment of two orphan adrenal diseases: classic congenital adrenal hyperplasia (CAH) and endogenous Cushing's syndrome (CS). Both of these diseases are associated with an overactive adrenal cortex causing excess steroid production. Millendo believes that nevanimibe represents an adrenal-specific approach that will address these diseases through the reduction of adrenal steroid production. Millendo is currently conducting Phase 2 clinical trial to assess the safety and efficacy of nevanimibe in subjects with endogenous Cushing’s syndrome and for the treatment of adult CAH.

Tosedostat is a proprietary orally bioavailable inhibitor of the M1 family of aminopeptidases with potential antineoplastic activity. Tosedostat is converted intracellularly into a poorly membrane-permeable active metabolite (CHR-79888) which inhibits the M1 family of aminopeptidases, particularly puromycin-sensitive aminopeptidase (PuSA), and leukotriene A4 (LTA4) hydrolase; inhibition of these aminopeptidases in tumor cells may result in amino acid deprivation, inhibition of protein synthesis due to a decrease in the intracellular free amino acid pool, an increase in the level of the proapoptotic protein Noxa, and cell death. There are several ongoing Phase 2 cooperative group-sponsored trials and investigator-sponsored trials evaluating the clinical activity of Tosedostat in combination with standard agents in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Amonafide L-malate (AS1413, Xanafide) is a DNA intercalator and topoisomerase II inhibitor that induces apoptosis by disrupting chromatin organisation independently of ATP. This is different from classical topoisomerase II inhibitors which induce apoptosis by causing extensive DNA damage. Amonafide L-malate is also able to evade P-glycoprotein and related transporters that contribute to multi-drug resistance. AS1413 had orphan drug status in both the U.S. and the E.U. for the treatment of AML and also received Fast Track status from the U.S. FDA for the treatment of secondary AML. Amonafide L-malate was originated by Xanthus Pharmaceuticals. It was added to Antisoma's pipeline through the acquisition of Xanthus Pharmaceuticals, Inc. in June 2008. Antisoma discontinued development of Amonafide L-malate after data from the open-label, international Phase III ACCEDE trial in over 420 patients showed that 600 mg/m 2 IV amonafide for 5 days plus cytarabine missed the primary endpoint of significantly improving initial remission rate, defined as the proportion of patients who achieve CR or CRi, vs. daunorubicin plus cytarabine.

Alisertib (MLN8237) is an orally available selective aurora A kinase inhibitor developed by Takeda. Alisertib inhibited AAK over ABK with a selectivity of more than 200-fold in cells and produced a dose-dependent decrease in bipolar and aligned chromosomes in the HCT-116 xenograft model, a phenotype consistent with AAK inhibition. Alisertib inhibited proliferation of human tumor cell lines in vitro and produced tumor growth inhibition in solid tumor xenograft models and regressions in in vivo lymphoma models. It is currently in phase II clinical trials for acute myeloid leukaemia; B cell lymphoma; brain cancer; mesothelioma; prostate cancer; small cell lung cancer.