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.

2-(4,6-DIMETHYLPYRIMIDIN-2-YL)-5-((2-FLUORO-6-(2H-1,2,3-TRIAZOL-2-YL)PHENYL)CARBONYL)OCTAHYDROPYRROLO(3,4-C)PYRROLE (Seltorexant, MIN 202), a small molecule, selective orexin receptor type-2 antagonist, is being developed by Minerva Neurosciences and Janssen Research & Development for the treatment of insomnia and major depressive disorder. Seltorexant has shown high in vitro affinity (affinity pKi =8.0 and 6.1 for OX2R and OX1R respectively) for the human OX2R and approximates two logs selectivity ratio versus its affinity for the OX1R. Seltorexant demonstrated a dose-dependent normalization of sleep and a trend towards improvement of subjective depressive symptoms in antidepressant-treated MDD patients with residual insomnia. Additionally, seltorexant’s favorable PK profile as a potential sedative-hypnotic drug was confirmed in a MDD population and did not demonstrate unacceptable adverse events or unwanted next-day CNS effects. Seltorexant is in phase II clinical trials for both insomnia and MDD.

p53 is a critical tumor suppressor and is the most frequently inactivated gene in human cancer. Inhibition of the interaction of p53 with its negative regulator MDM2 represents a promising clinical strategy to treat p53 wild-type tumors. AMG 232 is a potential best-in-class inhibitor of the MDM2-p53 interaction and is currently in clinical trials. Based on X-ray cocrystal structures a model of AMG 232 bound to MDM2 was developed. The model shows that the m-chlorophenyl, the p-chlorophenyl, and C-linked isopropyl fragments of AMG 232 bind to the Leu 26(p53), Trp 23(p53), and Phe 19(p53) pockets of MDM2, respectively. The carboxylic acid forms a salt bridge with His 96 and the isopropyl sulfone forms a novel interaction with the glycine shelf region of MDM2. AMG 232 in phase II in combination with trametinib and dabrafenib in subjects with metastatic melanoma; in phase I for the treatment of solid tumors, multiple myeloma and Acute Myeloid Leukemia.

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.

Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. Verinurad specifically inhibits URAT1 with a potency of 25 nM. High affinity inhibition of uric acid transport requires URAT1 residues Cys-32, Ser-35, Phe-365 and Ile-481. Unlike other available uricosuric agents, the requirement for Cys-32 is unique to verinurad. Verinurad doses as low as 2.5 mg produce significant sUA lowering in humans, and this greater reduction in sUA may lead to improved outcomes and medical benefits for patients with gout. Verinurad in monotherapy studies has been associated with increased urinary uric acid concentrations and low rates of serum creatinine (sCr) elevation. Verinurad combined with febuxostat decreased sUA dose-dependently while maintaining uric acid excretion similar to baseline. All dose combinations of verinurad and febuxostat were generally well tolerated.

Novartis Oncology (previously Novartis) is developing nazartinib (formerly EGF 816), a third generation mutant-selective tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), for the treatment of solid malignancies, with a focus on non-small cell lung cancer. Nazartinib is a covalent mutant-selective EGFR inhibitor, with Ki and Kinact of 31 nM and 0.222 min−1 on EGFR(L858R/790M) mutant, respectively. Upon oral administration, nazartinib covalently binds to and inhibits the activity of mutant forms of EGFR, including the T790M EGFR mutant, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. EGF816 preferentially inhibits mutated forms of EGFR including T790M, a secondarily acquired resistance mutation, and may have therapeutic benefits in tumors with T790M-mediated resistance when compared to other EGFR tyrosine kinase inhibitors. As this agent is selective towards mutant forms of EGFR, its toxicity profile may be reduced as compared to non-selective EGFR inhibitors which also inhibit wild-type EGFR.