PHA-680632 is potent inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 27 nM, 135 nM and 120 nM, respectively. It has 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, and VEGFR2/3. PHA-680632 is active on a wide range of cancer cell lines and shows significant tumor growth inhibition in different animal tumor models at well-tolerated doses. The mechanism of action of PHA-680632 is in agreement with inhibition of Aurora kinases. PHA-680632 in association with radiation leads to additive effects in cancer cells, especially in the p53-deficient cells. Combined ionising radiation (IR) and treatment of PHA-680632 (100–400 nM) prior to IR leads to an enhancement of radiation-induced Annexin V positive cells, micronuclei formation, and Brca1 foci formation only in HCT116 cells with deficient p53, other than the p53 wild-type counterparts. HA-680632 (15–60 mg/kg) inhibits tumor growth in mice xenografts models of HL60, A2780, and HCT116 cells, by reducing tumor cell proliferation and increasing apoptosis. PHA-680632 is the first representative of a new class of Aurora inhibitors with a high potential for further development as an anticancer therapeutic.

BAY-1082439 is an orally bioavailable inhibitor of the class I phosphoinositide 3-kinase (PI3K) alpha and beta isoforms with potential antineoplastic activity. PI3K alpha/beta inhibitor BAY1082439 selectively inhibits both PI3K alpha, including mutated forms of PIK3CA, and PI3K beta in the PI3K/Akt/mTOR pathway, which may result in tumor cell apoptosis and growth inhibition in PI3K-expressing and/or PTEN-driven tumor cells. By specifically targeting class I PI3K alpha and beta, this agent may be more efficacious and less toxic than pan PI3K inhibitors. Dysregulation of the PI3K/Akt/mTOR pathway is frequently found in solid tumors and results in increased tumor cell growth, survival, and resistance to chemotherapy and radiotherapy. PIK3CA, one of the most highly mutated oncogenes, encodes the p110-alpha catalytic subunit of the class I PI3K. PTEN, a tumor suppressor protein and negative regulator of PI3K activity, is often mutated in a variety of cancer cells.

BAY-87-2243 is a potent and selective hypoxia-inducible factor-1 (HIF-1) inhibitor. BAY 87-2243 inhibits HIF-1 reporter gene activity and CA9 protein expression with IC50 of 0.7 nM and 2 nM, respectively. In hypoxic lung cancer H460 cells, BAY-87-2243 suppresses HIF target gene expression, and inhibits HIF-1α protein accumulation. BAY-87-2243 showed dose-dependent in vivo antitumor efficacy in the H460 lung tumor xenograft model accompanied by a suppression of HIF-1a protein and HIF-1 target genes without any signs of toxicity or body weight loss. Further mode-of-action analyses revealed that BAY-87-2243 exerts its effect on the HIF pathway by blocking mitochondrial complex I activity and thereby reducing HIF protein levels under hypoxia. BAY-87-2243 had been in phase I clinical trials by Bayer for the treatment of malignancies. However, this study has been terminated for the drug-related adverse events.

Destruxin B, isolated from entomopathogenic fungus Metarhizium anisopliae, is one of the cyclodepsipeptides with antimicrobial, insecticidal and anticancer activities. Destruxin B, a specific and readily reversible inhibitor of vacuolar-type H(+)-translocating ATPase.

RI-1 is a cell-permeable RAD51 inhibitor that binds covalently to the protein surface at Cysteine 319. RI-1 disrupts homologous recombination in human cells. Also, it is an inhibitor of Bfl-1 protein. RI-1 represents a powerful tool for future investigations on mechanisms of DNA repair. RI-1 holds promise as an oncologic drug. In a glioma xenograft model, the Rad51 inhibitor RI-1 clearly enhanced the effect of lomustine on tumor growth.

BMS-794833 (N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-5-(4- fluorophenyl)-4-oxo-l,4-dihydropyridine-3-carboxamide) is an inhibitor of Met, VEGFR2, Ron, Axl and Flt-3 kinases. BMS-794833 demonstrated dose-dependent tumor growth inhibition following oral administration in xenograft models. In cell culture, BMS-794833 inhibited the proliferation of human tumor cell lines containing constitutively activated Met receptor. BMS-794833 is an active moety of pro-drug BMS-817378. Bristol-Myers Squibb and Simcere Pharmaceutical Group are developing BMS-817378 for treatment of cancer.

HS-173 is a potent PI3Kα inhibitor with IC50 of 0.8 nM. HS-173 inhibited the PI3K signaling pathway, and showed anti-proliferative effects on cancer cells. Also, HS-173 induced cell cycle arrest at the G(2)/M phase and apoptosis. In addition, HS-173 decreased the expression HIF-1α and VEGF which play an important role in angiogenesis. This effect was confirmed by the suppression of tube formation and migration assay in vitro. Furthermore, HS-173 diminished blood vessel formation in the Matrigel plug assay in mice. Therefore, HS-173 is considered as a novel drug candidate to treat cancer patients.

Adjudin (known as AF-2364) was developed as a male contraceptive drug, which induces reversible germ cell loss from the seminiferous epithelium by disrupting cell adhesion function between Sertoli and germ cells, in particular, elongating/elongate/round spermatids and spermatocytes but not spermatogonia. This drug was in phase II clinical trial for human. In addition was discovered, that adjudin could trigger mitochondrial dysfunction in cancer cells, apparently affecting the mitochondrial mass, inducing the loss of mitochondrial membrane potential and reducing cellular ATP levels and thus could be a potential drug for cancer therapy.

GSK2606414 is an orally bioavailable, potent, selective inhibitor of PERK. The drug may serve as a potential treatment for cancer and neurodegenerative diseases associated with the accumulation and aggregation of misfolded disease-specific proteins in the brain. GSK2606414 demonstrated good results on a mouse model of prion disease.

Erastin is antitumor agent, exhibiting selectivity for tumor cells bearing oncogenic RAS. Erastin is a ferroptosis activator; it induces oxidative, non-apoptotic cell death in tumors by acting directly on voltage-dependent anion channel 2 (VDAC2).