BAY-1125976 is an orally bioavailable inhibitor of the serine/threonine protein kinase AKT (protein kinase B) isoforms 1 and 2 (AKT1/2) with potential antineoplastic activity. AKT1/2 inhibitor BAY1125976 selectively binds to and inhibits the phosphorylation and activity of AKT1/2 in a non-ATP competitive manner, which may result in the inhibition of the phosphatidylinositol 3 (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. This may lead to both the reduction of cell proliferation and the induction of cell apoptosis in AKT-overexpressing tumor cells. The AKT signaling pathway is often deregulated in cancer and is associated with tumor cell proliferation, survival, and migration. BAY 1125976 is equally potent against Akt1 and Akt2 isoforms and up to 86 fold less potent against Akt3 It inhibits the Akt1 and Akt2 by binding into an allosteric binding pocket formed by kinase and PH domain. It inhibits cell proliferation in a broad panel of human cancer cell lines, particularly in breast and prostate cancer cell lines expressing estrogen or androgen receptors. It effectively blocks Akt signaling by inhibiting the phosphorylation of Akt and the downstream effectors, including eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), glycogen synthase kinase 3 beta (GSK3s), proline-rich Akt substrate 40 kDa (PRAS40), S6 ribosomal protein (S6RP), and 70 kDa ribosomal protein S6 kinase 1 (70S6K). BAY 1125976 exhibits strong in vivo efficacy in both cell line and patient-derived xenograft models such as the KPL4 breast cancer model (PIK3CAH1074R mutant), the MCF7 and HBCx-2 breast cancer models, and the AktE17K mutant driven prostate cancer (LAPC-4) and anal cancer (AXF 984) models.

PF-06840003 is a highly selective orally bioavailable Indoleamine 2,3-dioxygenase-1 (IDO-1) inhibitor with a potent antineoplastic activity. PF-06840003 reversed IDO-1-induced T-cell anergy in vitro. In vivo, PF-06840003 reduced intratumoral kynurenine levels in mice by >80% and inhibited tumor growth in multiple preclinical syngeneic models in mice, in combination with immune checkpoint inhibitors. A Phase 1 study of PF-06840003 in patients with Malignant Gliomas is ongoing.

CPG-52364 is a potent antagonist of toll-like receptors TLR7, TLR8, TLR9. The drug was developed by Coley Pharmaceutical Group (later acquired by Pfizer) for the treatment of immune diseases and reached phase I of clinical trials presumably for systemic lupus erythematosus. However, the development of CPG-52364 was terminated by unknown reason.

TBA-354, also known as SN31354, is a potent anti-tuberculosis drug candidate. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. TBA-354 is a promising next-generation nitroimidazole antitubercular agent. TBA-354 emerged from studies designed to identify a next generation nitroimidazole for TB. TB Alliance conducted the studies in collaboration with the University of Auckland and University of Illinois-Chicago. Once identified, TB Alliance further advanced TBA-354 through pre-clinical development and is now the sponsor of the Phase 1 study.

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.

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.

VTP-27999 is an alkyl amine renin inhibitor. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans. Vitae Pharmaceuticals was developing VTP 27999 for the treatment of chronic kidney disease. VTP 27999 was in phase I clinical development in the US. However, the product is no more on the company pipeline and it appears that the development has been discontinued.

VS-5584 is a potent and selective oral small molecule inhibitor of all 4 PI3K isoforms and mTORC1 and mTORC2. VS-5584 inhibits mTOR, PI3Kα/β/δ/γ with IC50 of 3.4 nM and 2.6-21 nM, respectively. Verastem has patent protection of VS-5584 through 2029, and has received orphan drug designation for VS-5584 in mesothelioma in the US and EU. Verastem is currently conducting a Phase 1 trial of VS-5584 in patients with advanced solid tumors and lymphomas.

4SC-202 is an epigenetic oncology compound with a unique therapeutic profile, which was developed by biotechnology company: 4SC. 4SC-202 works as a selective inhibitor of LSD1 (lysine-specific demethylase 1) and HDAC (histone deacetylase) 1, 2 and 3. 4SC-202 also strengthens the endogenous immune response to cancer tissue. This compound demonstrated successfully completed Phase I of the clinical study, where it was proved safe and well tolerated in patients with advanced hematologic cancer. In addition, 4SC-202 shows substantial anti-tumor activity in a broad range of cancer cell lines including hepatocellular carcinoma, Urothelial Carcinoma Cell Lines and colorectal cancer.