GSK-461364 is a potent, selective, reversible, ATP-competitive inhibitor of Plk1. GSK-461364 broadly inhibits cancer cell proliferation with differential survival outcome. GSK-461364 blocks cells in G2 and M phases of the cell cycle and causes M-phase caspase-3/caspase-7 activation. GSK-461364 is efficacious in xenograft tumor models. GlaxoSmithKline is developing GSK-461364 for the treatment of solid tumours and non-Hodgkin's lymphoma.

TAK-733 had been developed by Millennium Pharmaceuticals (subsidiary of Takeda) for the treatment of adult patients with advanced non-hematological malignancies. In 2015, Takeda discontinued this studies. TAK-733 is an inhibitor of MEK that exhibits anticancer chemotherapeutic activity. In tumor explant models, TAK-733 induces tumor regression. In colorectal cancer cells and melanoma cells, this compound suppresses cell growth. Additionally, TAK-733 decreases tumor growth and weight in animal models of lung cancer and melanoma.

SAR-405838 is an inhibitor of the interaction between the oncoprotein murine double minute 2 (MDM2) and p53. SAR-405838 was investigated in phase I clinical trials in patients with locally advanced/metastatic solid tumor with wild-type TP53 or with TP53 mutation prevalence below 40%. SAR-405838 had an acceptable safety profile with limited activity in patients with advanced solid tumors.

AZD-8186 is a potent and selective inhibitor of PI3Kβ and PI3Kδ with IC50 of 4 nM and 12 nM, respectively. AZD-8186 is currently in phase 1 clinical trials. Combination therapy using AZD-8186 with androgen deprivation results in long-lasting tumor regression, which persisted after treatment cessation.

Q203 (6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo [1,2-a]pyridine-3-carboxamide) is an an imidazopyridine antitubercular compound. Q203 targets the cytochrome b subunit (QcrB) of the cytochrome bc1 complex. This complex is an essential component of the respiratory electron transport chain of ATP synthesis. Q203 inhibited the growth of multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Q203 is a promising new clinical candidate for the treatment of tuberculosis.

GDC-0994 (RG7842) is a selective inhibitor of ERK1/2, also known as extracellular-signal-regulated kinases. Daily, oral dosing of GDC-0994 results in significant single-agent activity in multiple in vivo cancer models, including KRAS-mutant and BRAF-mutant human xenograft tumors in mice. GDC-0994 neither increases nor decreases phospho-ERK, suggesting that different ERK inhibitors have alternative mechanisms of action with respect to feedback signaling. GDC-0994 is currently advancing in a Phase 1 trial in patients with solid tumors.

ICI-118,551 is a selective subtype β2 adrenergic receptor (adrenoreceptor) antagonist. ICI-118,551 binds to the β2 subtype with at least 100 times greater affinity than to other subtypes of the beta adrenoceptor β1 or β3. Pharmacological experiments proved that the right shift of the norepinephrine dose-response curve by ICI-118,551 was mediated via a beta(2)-adrenoceptor/G(i/o) protein-dependent pathway enhancing NO production in the endothelium. These results were corroborated in beta-adrenoceptor and endothelial NO synthase knockout mice where ICI had no effect. ICI-118,551 increased vascular lumen diameter in lung sections and reduced pulmonary arterial pressure under normoxia and under hypoxia in the isolated perfused lung model. These effects were found to be physiologically relevant, because ICI-118,551 specifically decreased pulmonary but not systemic blood pressure in vivo. Thus, it has been suggested that ICI-118,551 is a pulmonary arterial-specific vasorelaxant and might be a potential novel therapeutic agent for the treatment of pulmonary arterial hypertension. It was also demonstrated that systemic topical administration of ICI 118,551 results in decreased intraocular pressure in both eyes of rabbits, indicating that at least part of the ocular hypotensive effect of topical ICI 118,551 is mediated through systemic absorption. However, ICI 118,551 did not lower blood pressure in hypertensive patients known to respond to therapy with atenolol or propranolol.

CUDC-305, is a novel heat shock protein 90 (HSP90) inhibitor with strong affinity for HSP90 alpha/beta, high oral bioavailability and potent anti-proliferative activity against a broad range of cancer cell lines (with a mean IC50 of 220 nmol/L), including many non-small cell lung cancer (NSCLC) cell lines which are resistant to standard-of-care (SOC) agents. In both laboratory and animal testing, CUDC-305 demonstrated high potency in vitro and/or in vivo across a wide range of cancers. Most notably, Curis scientists observed complete tumor regression following oral administration of CUDC-305 in a mouse xenograft model of acute myelogenous leukemia (AML). Tumor regression has also been observed after treatment of CUDC-305 in mouse xenograft models of breast, non-small cell lung, gastric cancer and glioblastoma brain cancers. In this preclinical testing, the compound also demonstrated an ability to effectively cross the blood brain barrier, and demonstrated an ability to extend survival in an intracranial glioblastoma model. Early stage toxicity studies suggest that CUDC-305 appears to have a better therapeutic window than several leading Hsp90 inhibitors in clinical development.

SGX523 is a selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase. SGX523 was able to inhibit HGF-induced cell migration and cell scatter. SGX523 inhibition of MET in vivo was associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers. The clinical development of SGX523, however, was discontinued at Phase I due to renal toxicity manifested by an early rise of serum blood urea nitrogen and creatinine.

TAK-960 is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor(IC50=1.5 nM) that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 had been in phase I clinical trials by Takeda for the treatment of solid tumours. It had also been in preclinical trials for the treatment of acute myeloid leukaemia. However, these studies were discontinued.