Chugai Pharma Europe is developing CH-5132799, a phosphatidylinositol-3-kinase (PI3K) inhibitor, for the treatment of solid tumours. CH-5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. CH-5132799 selectively inhibits class I PI3Ks, PI3Kα (IC50 = 0.014 uM ), PI3Kβ (IC50 = 0.12 uM ), PI3Kδ (IC50 = 0.50 uM ), PI3Kγ (IC50 = 0.036 uM ), but shows less inhibition of class II PI3Ks, class III PI3k and mTOR and also no inhibitory activity (IC50 > 10 uM) against 26 protein kinases. CH-5132799 exhibits more inhibitory activities against PI3Kα with oncogenic mutations E542K (IC50 = 6.7 nM), E545K (IC50 = 6.7 nM) and H1047R (IC50 = 5.6 nM) than wild-type PI3Kα. CH-5132799 treated breast cnacer KPL-4 cells, which harbor the PIK3CA mutation, phosphorylation of Akt and its direct substrates, PRAS40 and FoxO1/3a and phosphorylation of downstream factors, including S6K, S6 and 4E-BP1, are effectively suppressed. Cancer cell lines harboring PIK3CA mutations are significantly sensitive to CH-5132799. CH-5132799 is orally available and showed significant antitumor activity in PI3K pathway-activated human cancer xenograft models in mice. CH-5132799 is in phase I study to evaluate safety, pharmacokinetics and activity of CH-5132799 administered orally as a single agent in patients with advanced solid tumors.

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.

Ipatasertib (LCL161) binds to inhibitors of apoptosis proteins (IAPs) with high affinity and initiates the destruction of cIAP1 and cIAP2, which further induces apoptosis via caspase activation. Ipatasertib is advancing in clinical development including five Phase 2 trials in patients with Breast cancer, Multiple myeloma, Myelofibrosis, Small cell lung cancer and Ovarian cancer. The most common LCL161-related adverse events were nausea and vomiting.

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.

Tetrahydropalmatine is a tetrahydroprotoberberine isoquinoline alkaloid that is a primary active constituent of herbal preparations containing plant species of the genera Stephania and Corydalis. The levo isomer of THP (L-THP) appears to contribute to many of the therapeutic effects of these preparations. The pharmacological profile of L-THP, which includes antagonism of dopamine D1 and D2 receptors and actions at dopamine D3, suggests that it may have utility for treating addiction. Clinical trials where L-THP was used for the treatment of cocaine and heroin addiction have promising results. The clinical trial is planned for the treatment of schizophrenia. L-Tetrahydropalmatine is recorded in the Chinese pharmacopoeia.

Novartis Oncology (previously Novartis) is developing WNT-974 (formerly LGK 974), a first-in-class selective small molecule inhibitor of O-acyltransferase. WNT-974 is under development for the treatment of cancers that are driven by the Wnt pathway in a Wnt ligand-dependent manner. Upon oral administration, WNT-974 binds to and inhibits PORCN in the endoplasmic reticulum (ER), which blocks post-translational acylation of Wnt ligands and inhibits their secretion. This prevents the activation of Wnt ligands, interferes with Wnt-mediated signaling, and inhibits cell growth in Wnt-driven tumors. Porcupine, a membrane-bound O-acyltransferase (MBOAT), is required for the palmitoylation of Wnt ligands, and plays a key role in Wnt ligand secretion and activity. Wnt signaling is dysregulated in a variety of cancers

MK-8033 is a dual c-Met/Ron inhibitor, which is under investigation by Merck for the treatment of cancer.

LY3023414, an investigational drug, is a small molecule that that demonstrates activity against PI3K, mTOR, and DNA-PK in tumor cells, thereby inducing cell-cycle effects and inhibiting cancer cell viability. As shown in vitro LY3023414 inhibits the ability of PI3K and mTOR to phosphorylate substrates in the PI3K/mTOR pathway, one of the most frequently mutated pathways in cancer, leading to cancer progression and resistance to existing treatments. Downstream target inhibition by LY3023414 occurs rapidly via an intermittent “on/off” mechanism that may enhance the drug's clinical tolerability, which may in turn allow LY3023414 to overcome some of the toxicities associated with PI3K/mTOR inhibitors and potentially reduce the emergence of feedback mechanisms leading to resistance. The physicochemical and absorption properties of LY3023414 are favorable, as evidenced by the molecule's high solubility across a wide pH range and high oral bioavailability. On the basis of these findings, LY3023414 is currently being evaluated in clinical trials in patients with advanced cancer such as metastatic prostate cancer and non-small cell lung cancer in combination with other chemotherapeutic agents and in endometrial cancer as a monotherapy.

Cinobufotalin, the bufadienolide isolated from toad venom, has displayed antitumor activities in many in vitro systems. It has been shown that cinobufotalin induced significant apoptosis in cultured human lymphoma U-937 cells. It induced DNA fragmentation, mitochondrial membrane potential decrease, and reactive oxygen species (ROS) production in U-937 cells. Cinobufotalin induces cytotoxic effect in cultured lung cancer cells. Cinobufotalin (1/5 mg/kg, i.p. twice daily, for 7 days) significantly inhibited A549 xenograft growth in mice. Further, same cinobufotalin administration improved mice survival at week five. Cinobufotalin administration didn’t significantly affect mice body weight, indicating the relative safety of this regimen. Thus, cinobufotalin inhibits A549 xenograft growth in vivo and improves mice survival.

GSK 1059615, a pyridinylquinoline derivative, is a novel PI3K kinase and mTOR dual inhibitor. GSK1059615 was in phase I clinical trial in patients with solid tumors or lymphoma, but this study was terminated prematurely due to lack of sufficient exposure following single- and repeat dosing. In addition, recently was shown, that GSK 1059615 in xenograft mice models possessed anti-head and neck squamous cell carcinoma (HNSCC) cell activity.