EW-7197 is an orally bioavailable inhibitor of the serine/threonine kinase, transforming growth factor (TGF)-beta receptor type 1 (TGFBR1), also known as activin receptor-like kinase 5 (ALK5), with potential antineoplastic activity. EW-7197 is in phase I clinical trials for the treatment of solid tumors. Also, EW-7197 has a strong potential as an anti-fibrosis therapeutic agent.

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

Pfizer was developing PF-03814735, an orally administered, reversible inhibitor of the Aurora A and Aurora B kinases. In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1 (Thr 232, a sensitive marker of Aurora1 activity, with IC50 ~ 20 nM), phosphohistone H3 (with IC50 50 nM), and phospho-Aurora2 (with IC50 150 nM). PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells. A recent research indicates small cell lung cancer (SCLC) and, to a lesser extent, colon cancer lines are very sensitive to PF-03814735. The status of the Myc gene family and retinoblastoma pathway members significantly correlates with the efficacy of PF-03814735. PF-03814735 was under Phase I trials for patients with advanced solid tumors, but later this research was discontinued.

The sesquiterpene lactone thapsigargin is found in the plant Thapsia garganica L., and is one of the major constituents of the roots and fruits of this Mediterranean species. In 1978, the first pharmacological effects of thapsigargin were established and the full structure was elucidated in 1985. Thapsigargin is a potent inhibitor of Sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) and is widely used to study Ca2+-signaling. Thapsigargin is a non-cell-type specific toxin with documented ability to kill a broad spectrum of cancer cell lines as well as normal endothelial cells, fibroblasts and osteoblasts. It induces a rapid and pronounced increase in the concentration of cytosolic calcium, due to blockade of the Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA) pump to which it binds with high affinity. The increase in cytosolic calcium leads to induction of apoptosis and ensuing cell death. A prodrug, G-202 (mipsagargin) has been designed to target the blood vessels of cancer cells; the death of these blood vessels then leads to tumor necrosis. G-202 consists of a cytotoxic analog of thapsigargin coupled to a masking peptide which inhibits its biologic activity until proteolytic cleavage at the tumor site. The first clinical trials of this drug were initiated in 2008 for the treatment Advanced Solid Tumors.

The receptor tyrosine kinase c-Met is an attractive target for therapeutic blockade in cancer. MK-2461 is a novel ATP-competitive multitargeted inhibitor of activated c-Met, was synthesized by Merck and was investigated in phase I of clinical trial for the potential treatment of patients with advanced solid tumors.

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.

Voruciclib (also known as P1446A-05) is a flavone-based, potent and selective CDK 4/6 inhibitor with activity in multiple BRAF-mutant and wild type cell lines. It is currently in clinical trials in combination with BRAF inhibitor (PLX4032) to treat advanced BRAF-mutant melanoma. Voruciclib has significant inhibitory activity against cutaneous and uveal melanoma. Mechanistic studies revealed that P1446A-05 inhibits phosphorylation targets of CDK members, and induces cell cycle arrest and apoptosis irrespective of melanoma genotype or phenotype. Voruciclib Hydrochloride is in phase I clinical trials by Piramal Life Sciences for the treatment of chronic lymphocytic leukaemia and malignant melanoma.

VLX600 - is a lipophilic cation-based triazinoindolyl-hydrazone compound and mitochondrial oxidative phosphorylation (OxPhos) inhibitor, with potential antineoplastic activity. VLX600 is designed to increase the efficacy of radiotherapy and to kill cancer cells that survive traditional chemotherapy. VLX 600 is a small molecule that inhibits deubiquitinating enzymes USP14 (a ubiquitin thiolesterase) and UCHL5 (a carboxypeptidase). Upon infusion, in normal cells and proliferating tumor cells where glucose is readily available, inhibition of OxPhos by VLX600 induces a hypoxia-inducible factor 1-alpha (HIF-1alpha)-dependent shift to, and an increase in glycolysis. Glycolysis alone does not produce enough energy to support the growth of tumor cells in this environment, and the induction of autophagy occurs. In the metabolically compromised tumor microenvironment, the availability of oxygen and glucose is limited due to poor vascularization and perfusion of tumor micro-areas. Tumor cells growing in this environment are thus unable to compensate for decreased mitochondrial function by increasing glycolysis. This leads to nutrient depletion, decreased energy production, induction of autophagy, tumor cell death and an inhibition of cell proliferation in quiescent tumor cells. Mitochondrial OxPhos, which is hyperactivated in cancer cells, plays a key role in the promotion of cancer cell proliferation. VLX-600 is in phase I clinical trials for the treatment of solid tumours. This compound was originally jointly discovered and developed by Vivolux and Karolinska Institute.

LTX-315 is a cationic amphipathic peptide that preferentially permeabilizes mitochondrial membranes, thereby causing partially BAX/BAK1-regulated, caspase-independent necrosis. The oncolytic effect of LTX-315 involves a unique immunogenic cell death targeting the mitochondria with subsequent release of danger-associated molecular pattern molecules. This initial targeting of the mitochondria is followed by disintegration of other cytoplasmic organelles resulting ineffective release of additional danger signals and a broad repertoire of tumour antigens and finally lysis of plasma membrane (necrosis). Preclinical and clinical studies have demonstrated LTX-315`s unique ability to reshape the tumour microenvironment by inducing the effective release of danger signals, chemokines and a broad repertoire of tumour antigens. These properties of LTX-315 results in enhanced infiltration of activated CD 8 T cells and Th1 responses. This ability to convert non-T cell inflamed tumours to T cell inflamed tumours makes LTX-315 an ideal combination partner with other types of immunotherapy, including immune checkpoint inhibitors/agonists, vaccines, and T cell-based therapies. Both preclinical and clinical studies have confirmed LTX-315s ability to induce a systemic anticancer immune response when injected locally into tumours resulting in complete or partial regression of injected and non-injected tumours (i.e. abscopal effect). Preclinical studies have demonstrated strong synergy with immune-checkpoint blockade which have given the scientific rationale for initiating combinations studies with Ipilimumab and Pembrolizumab in melanoma and TNB cancer patients respectively. Phase Ib study combining LTX-315 with ipilimumab (anti-CTLA4) in malignant melanoma patients, as well as LTX-315 with pembrolizumab (anti-PD-1) in metastatic breast cancer patients, is ongoing.

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.