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.

GSK690693 is an aminofurazan derivative, a novel ATP-competitive, low-nanomolar pan-Akt kinase inhibitor. It is selective for the Akt isoforms versus the majority of kinases in other families; however, it does inhibit additional members of the AGC kinase family. GlaxoSmithKline was developing this compound for the treatment of lymphoma solid tumours but the clinical development of this compound was terminated due to the associated side-effect of transient hyperglycemia.

XL019 is a potent and selective JAK2 inhibitor. XL019 shows 50-fold or greater selectivity for JAK2, versus a panel of over 100 serine/threonine and tyrosine kinases, including other members of the JAK family. XL019 is non-selective for JAK2V617F or wild-type JAK2 and potently inhibits STAT3 and STAT5 phosphorylation in cells harboring either JAK2V617F or wild-type JAK2. Unfortunately, XL019 treatment was associated with the unexpected occurrence of neurotoxicity. Phase I clinical trials have been terminated.

AZD1480 is a novel agent that inhibits Janus-associated kinases 1 and 2 (JAK1 and JAK2). In phase I study, AZD1480 was administered as an oral QD or b.i.d. monotherapy to patients with advanced solid tumors at eight dose levels in the ranges of 10–70 mg QD and 20–45 mg b.i.d. using a standard 3 3 design. AZD1480 had fast absorption, fast elimination, and dose-dependent increase in exposure from 10 mg to 50 mg. Unusual toxicity profile and overall lack of clinical activity led to discontinuation of development of AZD1480.

OSI-930 (now SIM-930) is a potent, oral small-molecule receptor tyrosine kinase inhibitor, which acts predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. OSI-930 has a pharmacokinetic-pharmacodynamic profile distinct from other RTK inhibitors, with potent antitumor activity in multiple xenograft models. OSI-930 passed through phase I clinical trial in the USA (in patients with advanced solid tumors) and recieved the clinical approval by China FDA after being out-licensed to Simcere Pharma in China.

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.

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.