NLG919 is a novel small-molecule IDO-pathway inhibitor. NLG919 potently inhibits this pathway in vitro and in cell-based assays. It is orally bioavailable and has a favorable pharmacokinetic and toxicity profile. In mice, a single oral administration of NLG919 reduces the concentration of plasma and tissue Kyn by ∼ 50%. Using IDO-expressing human monocyte-derived DCs in allogeneic MLR reactions, NLG919 potently blocked IDO-induced T cell suppression and restored robust T cell responses with an ED50=80 nM. Similarly, using IDO-expressing mouse DCs from tumor-draining lymph nodes, NLG919 abrogated IDO-induced suppression of antigen-specific T cells (OT-I) in vitro. In vivo, in mice bearing large established B16F10 tumors, administration of NLG919 markedly enhanced the anti-tumor responses of naïve, resting pmel-1 cells to vaccination with cognate hgp100 peptide plus CpG-1826 in IFA

AZD-3759 is an oral inhibitor of both wild-type and mutant EGFR with IC50 values in nanomolar range. The drug was discovered by AstraZeneca for the treatment of non-small-cell lung cancer with CNS metastases. AZD-3759 can penetrate the blood-brain barrier and was confirmed to be effective in vitro with NSCLC cell lines as well as in mouse model of brain metastases. AZD-3759 is currently in Phase 1 clinical trial.

VX-970 (VE-822) is an ATR kinase inhibitor. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. Vertex Pharmaceuticals is developing VX 970 for the treatment of advanced solid tumours. Phase I/II development is underway in the US for small-cell lung cancer and in the UK for solid tumours. Phase II development of VX 970 as a combination therapy in urogenital cancer, ovarian, primary peritoneal and fallopian tube cancer indications is underway in the US.

Raxatrigine also known as GSK1014802 and CNV-1014802, is a novel analgesic under development by Convergence Pharmaceuticals for the treatment of lumbosacral radiculopathy (sciatica) and trigeminal neuralgia (TGN). It is a novel state dependent small molecule sodium channel blocker that preferentially inhibits the Nav 1.7 ion channel, a therapeutic target implicated by genetics in human pain conditions. Raxatrigine is thought to penetrate the central nervous system and block Nav channels in a novel manner. CNV1014802 was granted orphan drug designation in 2013 by the US Food and Drug Administration (FDA) for the treatment of trigeminal neuralgia.

SAR407899 is a potent, ATP-competitive Rho kinase inhibitor. It antihypertensive action in animals. Sanofi is developing SAR 407899 for the treatment of microvascular angina (Syndrome X). It was previously being developed in clinical trials for the treatment of diabetic neuropathies, diabetic nephropathies, erectile dysfunction, pulmonary hypertension, hypertension and kidney disorders, but development was discontinued for those indications.

Nastorazepide (Z-360) is a selective, orally available, gastrin/cholecystokinin 2 (CCK-2) receptor antagonist with potential antineoplastic activity. Z-360 binds to the gastrin/CCK-2 receptor, thereby preventing receptor activation by gastrin, a peptide hormone frequently associated with the proliferation of gastrointestinal and pancreatic tumor cells. It is currently under development as a therapeutic drug for pancreatic cancer, gastroesophageal reflux disease and peptic ulcers. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue.

Edaglitazone have a clear PPAR-gamma agonist profile, with predominant PPAR-gamma activity and little PPAR-alpha activity. Edaglitazone was reported to significantly improve insulin sensitivity and enhance the rate of glucose oxidation in both the presence and absence of insulin. Additional studies have shown that edaglitazone affects muscle glucose metabolism by additional mechanisms other than PPAR-gamma activation. Phase I clinical studies have revealed that edaglitazone is well-tolerated and capable of significantly improving glucose homeostasis. Edaglitazone had been in phase II clinical trials for the treatment if type 2 diabetes. However, this research has been discontinued.

Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. Enzastaurin (LY317615) is a potent PKCβ selective inhibitor. Enzastaurin suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis. Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. Eli Lilly discontinued development of enzastaurin after top-line data from the double-blind, international Phase III PRELUDE trial in 758 DLBCL patients showed that enzastaurin missed the primary endpoint of improving DFS vs. placebo.

Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. Enzastaurin (LY317615) is a potent PKCβ selective inhibitor. Enzastaurin suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis. Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. Eli Lilly discontinued development of enzastaurin after top-line data from the double-blind, international Phase III PRELUDE trial in 758 DLBCL patients showed that enzastaurin missed the primary endpoint of improving DFS vs. placebo.

PND-1186, also known as SR-2156 and VS-4718, is a potent FAK inhibitor with a 50% inhibitory concentration (IC50) of 1.5 nM in vitro. PND-1186 has an IC50 of ~100 nM in breast carcinoma cells. PND-1186 is currently being evaluated in a Phase 1 trial in patients with advanced solid tumors. In addition, an ongoing collaboration with Wash U is evaluating PND-1186 in combination with gemcitabine and Abraxane in 1st line pancreatic cancer.