Nitroarginine (LNNA), an analog of L-arginine, is a competitive inhibitor of nitric oxide synthase which has been shown to prevent glutamate toxicity. Nitroarginine has been experimentally tested for its ability to prevent ammonia toxicity and ammonia-induced alterations in brain energy and ammonia metabolites. The Kd value (k(off)/k(on)) of bovine brain cNOS for LNNA was 15 nM. In contrast to the potent and slow onset of LNNA inhibition of brain cNOS, LNNA inhibition of inducible mouse macrophage NOS (iNOS) was weaker (Ki = 4.4 uM) and rapidly reversible. Thus, LNNA was a 300-fold more potent inhibitor of bovine brain cNOS than mouse macrophage iNOS. By inhibiting nitric oxide synthase LNNA causes the selective reduction of blood flow to tumor cells. Despite the potential of LNNA to function as an adjuvant in cancer therapies, its poor solubility and stability have hindered the development of an injectable formulation of LNNA that is suitable for human administration.

Mevastatin (compactin or ML-236B) is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This drug induces apoptosis and arrest of cancer cells in G1 phase. Therapeutic effects of mevastatin on serum level of lipoproteins and unbiquinone-10 in patients with familial hypercholesterolemia were investigated. However, that study was discontinued. In addition, mevastatin was investigated for the treatment of melanoma. It was suggested, that mevastatin was unlikely to prevent melanoma at standard doses. However, higher doses could have a role to play in adjuvant therapy by inhibiting growth and invasion of melanoma cells. Also was revealed, that mevastatin increased histone deacetylase inhibitor, LBH589-induced cell death in triple-negative breast cancer (TNBC) cells.

AZD-3759 is an oral inhibitor of both wild-type and mutant EGFR with IC50 values in nanomolar range. The drug was discovered by AstraZeneca for the treatment of non-small-cell lung cancer with CNS metastases. AZD-3759 can penetrate the blood-brain barrier and was confirmed to be effective in vitro with NSCLC cell lines as well as in mouse model of brain metastases. AZD-3759 is currently in Phase 1 clinical trial.

ETC-159 (ETC-1922159) is an inhibitor of membrane-bound O-acyltransferase porcupine. Porcupine palmitoleates Wnt and this modification is essential for binding to chaperone WLS and Frizzled receptors and is therefore required for the activity of all Wnts. ETC-159 exerts antineoplastic properties both in vitro and in vivo due to inhibition of Wnt pathway. ETC-159 development has progressed to phase I clinical trial.

VTP-27999 is an alkyl amine renin inhibitor. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans. Vitae Pharmaceuticals was developing VTP 27999 for the treatment of chronic kidney disease. VTP 27999 was in phase I clinical development in the US. However, the product is no more on the company pipeline and it appears that the development has been discontinued.

H3B-6527 is a highly selective covalent FGFR4 inhibitor with at least 250-fold selectivity over FGFR1-3. H3B-6527 inhibits FGFR4 signaling, proliferation, and leads to apoptosis in Hepatocellular carcinoma (HCC) cell line. Treatment on Hep3B cells leads to robust activation of caspase-3/7, an apoptotic marker, in a concentration-dependent manner, indicating FGFR4 inhibition by H3B-6527 leads to cell death in HCC cell lines. In the Hep3B human HCC xenograft mouse model, H3B-6527 shows dose-proportional plasma exposures and greater than dose-proportional tumor exposures within the dose range evaluated (30, 100, and 300 mg/kg). Oral treatment of H3B-6527, twice daily, inhibits xenograft growth in a dose-dependent manner in nude mice, with the 300 or 100 mg/kg twice daily, significantly inhibiting tumor growth in both Hep3B subcutaneous and orthotopic xenograft model and causing tumor regressions in the subcutaneous xenograft model.