AST-1306, also known as Allitinib, is an orally active potent, selective, irreversible inhibitor of the HER family of receptor tyrosine kinases. AST-1306 inhibits the enzymatic activities of wild-type epidermal growth factor receptor (EGFR) and ErbB2 as well as EGFR resistant mutant in both cell-free and cell-based systems. AST1306 potently suppressed tumor growth in ErbB2-overexpressing adenocarcinoma xenograft and FVB-2/N(neu) transgenic breast cancer mouse models. Allitinib is in Phase I clinical trial for the treatment of advanced solid tumors. Serious adverse effects detected were: diarrhea, dehydration and hyperbilirubinemia.

IPI-549 is an orally bioavailable, highly selective small molecule inhibitor of the gamma isoform of phosphoinositide-3 kinase (PI3K-gamma) with potential immunomodulating and antineoplastic activities. Upon administration, IPI-549 prevents the activation of the PI3K-gamma-mediated signaling pathways, which may lead to a reduction in cellular proliferation in PI3K-gamma-expressing tumor cells. In addition, this agent is able to modulate anti-tumor immune responses and inhibit tumor-mediated immunosuppression. Unlike other isoforms of PI3K, the gamma isoform is overexpressed in certain tumor cell types and immune cells; its expression increases tumor cell proliferation and survival. By selectively targeting the gamma isoform, PI3K signaling in normal, non-neoplastic cells is minimally or not affected, which results in a reduced side effect profile. Preclinical data in multiple solid tumor models have demonstrated that IPI-549 targets immune cells and alters the immune-suppressive microenvironment, promoting an anti-tumor immune response that leads to tumor growth inhibition. A Phase 1 study of IPI-549 in patients with advanced solid tumors is ongoing.

AZD-6482 is being developed by AstraZeneca to evaluate its therapeutic effects in the treatment of thrombosis. AZD-6482 is essentially a PI3K-beta inhibitor. It is a PI3Kβ inhibitor with IC50 of 10 nM, 8-, 87- and 109-fold more selective to PI3Kβ than PI3Kδ, PI3Kα and PI3Kγ in cell-free assays. by targeting PI3Kβ, AZD-6482 specifically inhibits thrombosis without interfering with normal haemostasis. Therefore, AZD-6482 is used as an anti-thrombotic drug for the prophylaxis of thrombotic disorders. AZD-6482 was in phase I trials by AstraZeneca for the prevention of thrombosis. However, the study was discontinued.

LY-3000328 is a Cathepsin S inhibitor with excellent in vitro potency and selectivity against other cysteine proteases. LY-3000328 is currently in clinical trials. Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cathepsin S may provide a new treatment for AAA.

CGM-097, a novel, highly optimized, and selective inhibitor of the p53-Mdm2 interaction. CGM-097 binds to human Mdm2 protein with a Ki value of 1.3 nM, activates p53 in human cells and induces robust p53-dependent cell cycle arrest and apoptosis in human p53 wild-type tumor cells. Its activity and selectivity has been tested and confirmed across a large panel of cancer cell lines from the Cancer Cell Line Encyclopedia. CGM-097 displays desirable pharmacokinetic and pharmacodynamic profiles in animals together with excellent oral bioavailability, which triggers rapid and sustained activation of p53-dependent pharmacodynamic biomarkers resulting in tumor regression in multiple xenografted models of p53 wild-type human cancer. The validation and understanding of its mechanism of action, the overall favorable drug-like properties and the characterization of its on-target toxicological profile in preclinical species strongly supported the initiation of Phase I clinical trials with CGM-097 in pre-selected patients with p53 wild-type tumors.

TAK-243 (MLN7243) is a small molecule inhibitor of ubiquitin-activating enzyme (UAE), with potential antineoplastic activity, which was developed by Takeda Oncology, Millennium. MLN7243 binds to and inhibits UAE, which prevents both protein ubiquitination and subsequent protein degradation by the proteasome. This inhibits tumor cell proliferation and survival. UAE, also called ubiquitin E1 enzyme (UBA1; E1), is more active in cancer cells than in normal, healthy cells. Currently, TAK-243 is in phase I clinical trial evaluating safety, tolerability, pharmacokinetics, pharmacodynamics against advanced malignant solid tumors phase.

ACT-462206 is a new, potent, and selective dual orexin receptor antagonist that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. ACT-462206 shows anxiolytic-like properties in rodents without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia and was in phase I of clinical trial, but this research has been discontinued.

PF-06273340 is a brain penetrant, orally available and potent tropomyosin-related kinase (Trk) inhibitor. PF-06273340 has a low metabolic turnover in Human liver microsomes and hepatocytes is a good substrate for efflux transporters P-glycoprotein and Breast cancer resistance protein (BCRP) and have moderate passive permeability. PF-06273340 was investigated in Phase I clinical trials for the treatment acute and chronic pain. However clinical development has been discontinued.

LY2811376 is a non-peptide inhibitor of BACE1 selective over BACE2. It showed robust central reduction of amyloid-β in humans.

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.