Blu-285 is a potent and selective inhibitor for hematologic malignancies with KIT Exon 17 Mutations. BLU-285 has demonstrated biochemical in vitro activity on the KIT exon-17 mutant enzyme, KIT D816V. Cellular activity of BLU-285 on KIT D816 mutants was measured by autophosphorylation in the human mast cell leukemia cell line HMC1.2, and the P815 mouse mastocytoma cell line with IC50= 4 and 22 nM, respectively. In vivo BLU-285 was well tolerated and has demonstrated dose-dependent antitumor efficacy. Complete tumor growth inhibition and ≥ 75% KIT kinase inhibition was observed with 10 mg/kg once daily, oral dosing of BLU-285 in the aggressive KIT exon 17 mutant driven P815 mastocytoma model grown as a solid tumor allograft as well as in a disseminated model of the disease. BLU-285 was also well tolerated in this in vivo model and had no adverse effects on body weight at either dose.

MK-5108 is a small molecule inhibitor of AuroraA kinase with high selectivity versus Aurora-B and C. It was tested in phase I study against advanced or refractory solid tumors both as a monotherapy or in combination with docetaxel, but this study was terminated early due to toxicities at MK-5108 doses below the anticipated PK exposure target.

E-7090 is a novel selective inhibitor of fibroblast growth factor receptors, that displays potent anti-tumor activity. It is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. E-7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses E-7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E-7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E-7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR. Furthermore, E-7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. It is being investigated in a Phase I clinical trial for treatment of patients with solid tumors.

PAK4-IN-1 (KPT-9274) is a first-in-class, orally bioavailable, small molecule immunometabolic modulator that works through non-competitive dual inhibition of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). Co-inhibition of these targets is believed to lead to synergistic anti-tumor effects through suppression of ß-catenin by blocking PAK4, leading to both immune cell activation and inhibition of tumor growth, energy depletion through NAMPT inhibition, blockade of DNA repair, cell cycle arrest and ultimately apoptosis. KPT-9274 may therefore have both immune-activating and direct antitumor effects. In contrast, normal cells are less sensitive to inhibition by KPT-9274 due in part to their relative genomic stability and lower metabolic demands. Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc. KPT-9274 demonstrated the expected on-target effects in this mouse model. KPT-9274 can reduce the steady state level of PAK4 protein in triple negative breast cancer cells. Oral administration of KPT-9274 reduces tumorigenesis in mouse models of human triple negative breast cancer. KPT-9274 is a novel therapeutic option for triple negative breast cancer therapy. KPT-9274 is being evaluated in a phase I human clinical trial in solid tumors and lymphomas, which will allow this data to be rapidly translated into the clinic for the treatment of RCC.

Darglitazone is a member of the thiazolidinedione class of drugs and an agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ), an orphan member of the nuclear receptor superfamily of transcription factors. It has a variety of insulin-sensitizing effects, such as improving glycemic and lipidemic control, and is used in the treatment of metabolic disorders such as type II diabetes. Darglitazone sodium had been in phase I clinical trials by Pfizer for the treatment of type 2 diabetes. However, this study has been discontinued.

PYM50018 (also known as Myogane or SARSAGENIN) has demonstrated neuroprotective effects in several preclinical models. It was observed that PYM50018 protects against neuronal damage, increases neurite outgrowth, reverses oxidative damage and reversed neuronal apoptosis. PYM50018 is in phase I clinical study for the treatment of amyotrophic lateral sclerosis (ALS).

Irsogladine, a mucosal protective drug, was developed in Japan for the treatment of peptic ulcer disease and acute gastritis. Irsogladine increases intracellular cyclic adenosine 3',5'-monophosphate content via non-selective inhibition of phosphodiesterase isozymes and exhibits gastric cytoprotection partly mediated by endogenous nitric oxide. These effects may account for a variety of actions of irsogladine in the gastrointestinal tract, including facilitation of gap junctional intercellular communication, inhibition of the reduced gastric mucosal blood flow response, suppression of reactive oxygen generation and so on.

Turofexorate Isopropyl (XL335) is a potent, selective, and orally bioavailable FXR agonist. Binds to the ligand-binding domain (LBD) of human FXR. Turofexorate Isopropyl resides in a predominately hydrophobic pocket with only a few polar atoms making contact with WAY-362450. Turofexorate Isopropyl promotes transcription of the human BSEP, human SHP, and mouse IBABP genes utilizing reporter constructs with EC50 of 17, 230, and 33 nM, respectively in promoter assays. Turofexorate Isopropyl had been in phase I clinical trials for the treatment of hyperlipidemia. This compound was originally discovered by Exelixis Pharmaceuticals, then licensed to Wyeth (now a wholly-owned subsidiary of Pfizer). However, the studies were discontinued.

Sulrnazole (the former AR-L 115 BS) is a benzimidazole derivative with positive inotropic, positive chronotropic and vasodilator effects. Sulrnazole also has been shown to improve cardiac index and reduce pulmonary capillary wedge pressure without significant change in heart rate or arterial pressure. Intravenous administration caused a 217 per cent increase in cardiac output with a 25 per cent decrease in pulmonary wedge pressure. Short-term oral administration resulted in a 317 per cent increase in cardiac index and a 317 per cent increase in ejection fraction. Side effects have included visual blurring and transient colour blindness. Sulmazol has been demonstrated to improve regional wall motion in patients with ischemic heart disease and to abolish pacing-induced ischemia. Sulrnazole is an A1 adenosine receptor antagonist. It is also a phosphodiesterase inhibitor.

Loxoribine [RWJ 217C7] is an immunostimulant which was developed by Johnson and Johnson. It is a selective agonist for TLR7 (Toll-like receptor 7), which possesses antitumor and antiviral properties and was investigated in a rat model of endometriosis and in addition, in phase I of a clinical trial for patients with advanced cancer.