HKI-357 is a potent, dual irreversible inhibitor of ErbB2 (HER2) and EGFR. HKI-357 suppresses ligand-induced EGFR autophosphorylation and cell proliferation in NCI-H1975 cells containing L858R and T790M mutations.

CUDC-101 is a multi-targeted agent designed to inhibit epidermal growth factor receptor (EGFR), human epidermal growth factor receptor Type 2 (Her2) and histone deacetylase (HDAC). This drug synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. Thus, a single compound may offer greater therapeutic benefits, which is verified in clinical trial phase I for the treatment patients with advanced head and neck, gastric, breast, liver, and non-small cell lung cancer tumors. In April 2013, CURIS, INC determined that they would discontinue enrolling patients in phase 1 expansion trial of the intravenous formulation of CUDC-101, and that the future development of CUDC-101 would be dependent on our ability to successfully develop an oral formulation of CUDC-101. However, the efforts to develop an effective oral formulation with improved bioavailability have not resulted in significant improvements when compared to the intravenous formulation of CUDC-101. As a result, at this time CURIS no longer plan to make material investments in this program.

Amgen is developing AMG-900, an orally active, small molecule aurora kinase A, B and C inhibitor for the treatment of solid tumours and haematological malignancies. In tumor cells, AMG-900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG-900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG-900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG-900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG-900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG-900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG-900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.

XL-019 is a potent inhibitor of JAK2 (IC50 = 2 nM), and is selective for JAK2 versus the other members of the JAK kinase family (JAK1 IC50 = 130 nM, JAK3 IC50 = 250 nM, TYK2 IC50 = 340 nM). It is active against both wild type and mutationally activated forms of JAK2, and showed good oral bioavailability and pharmacodynamic properties in preclinical studies. Activating mutations in JAK2 are frequently observed in patients with myeloproliferative disorders such as myelofibrosis, polycythemia vera and essential thrombocythemia. JAK2 activity is also upregulated via multiple mechanisms in many lymphomas and solid tumors. XL-019 was being developed by Exelixis for the treatment of myelofibrosis and polycythaemia vera.

ASP-3026 is a ALK tyrosine kinase receptor inhibitor which was developed by Astellas Pharma for the treatment of cancer conditions. The drug is being tested in phase I of clinical trials in patients with solid tumors, B-cell lymphoma and non-small cell lung carcinoma. The drug was discontinued for strategic reasons.

Salvinorin A has been reported to be the most potent naturally occurring hallucinogen, with an effective dose in humans in the 200- to the 1,000-μg range when smoked; it has been reported to induce an intense hallucinatory experience in humans, with a typical duration of action being several minutes to an hour or so. Salvinorin A is a highly selective agonist of the kappa-opioid receptor (KOR) with few off-target effects. It is a potent and selective dilator of the cerebral vasculature, exhibits rapid penetration through the blood-brain barrier, has potent anti-inflammatory properties, and has the ability to preserve neurovascular unit integrity. As such, salvinorin A is an ideal compound for the prevention and treatment of cerebral vasospasm following subarachnoid hemorrhage.

PX-478 is a highly potent and selective Hypoxia-inducible Factor-1α (HIF-1α) inhibitor. It lowers HIF-1α protein levels and HIF-1 transactivation in hypoxia and in normoxia in a variety of cancer cell lines, but has a more pronounced effect on translation of proteins, such as HIF-1α in hypoxia. PX-478 also enhances the radiosensitivity of prostate carcinoma PC3 cells. Its inhibition is independent of the tumor suppressor genes VHL and p53, and may be related to derangements in glucose uptake and metabolism due to inhibition of glucose transporter-1 (Glut-1). PX-478 has excellent activity against established human tumor xenografts, inducing tumor regressions with prolonged growth delays which correlate positively with HIF-1 levels. In high-fat-diet mice, PX-478 causes reduced fibrosis and fewer inflammatory infiltrates in their adipose tissues. PX-478 had been in phase I clinical trials by for the treatment of lymphoma and solid tumors. However, this research has been discontinued.

OSI-027 is an orally bioavailable mammalian inhibitor of mTOR kinase and has antineoplastic activity. OSI-027 binds to and inhibits of the catalytic site of mTOR, which is a central part of two protein complexes, mTORC1 and mTORC2, which may result in tumor cell apoptosis and a decrease in tumor cell proliferation. OSI-027 is in phase I clinical trial for the investigation on patients with advanced solid tumors or lymphoma.

ARQ-621 is a small-molecule inhibitor of the kinesin-related motor protein Eg5 with potential antineoplastic activity. Eg5 kinesin-related motor protein inhibitor ARQ 621 selectively inhibits the activity of Eg5, which may result in mitotic disruption, apoptosis and cell death. The ATP-dependent Eg5 kinesin-related motor protein (also known as KIF11 or kinesin spindle protein-5) is a plus-end directed kinesin motor protein involved in the regulation of spindle dynamics, including assembly and maintenance, during mitosis. In proliferation assays, ARQ-621 showed broad spectrum cytotoxicity against a panel of human cancer cell lines, with cell cycle analysis confirming a G2/M arrest followed by apoptosis. When administered intraperitoneally to nude mice bearing human pancreatic tumors (MIA PaCa-2), complete tumor stasis was achieved with a 6.25 mg/kg dose 3 times weekly for 4 weeks. At the completion of ARQ-621 dosing, the mice showed hematology profiles indistinguishable from untreated controls with no evidence of bone marrow toxicity. A phase I trial has been completed, however research has being discontinued.

LX-7101 (Lexicon Pharmaceuticals) was advanced to Phase-I clinical trials for treatment open-angle glaucoma or ocular hypertension. This drug is a potent inhibitor of LIM-kinase 2 (LIMK2) kinase and inhibits to less extent LIMK1 and Rho-associated protein kinase 2 (ROCK2).