Capmatinib (INC280, INCB028060), is an orally bioavailable inhibitor of the proto-oncogene c-Met (hepatocyte growth factor receptor [HGFR]) with potential antineoplastic activity. Novartis acquired Incyte's capmatinib, which is in Phase II clinical trial as monotherapy in patients with advanced hepatocellular carcinoma. Capmatinib selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways. This may induce cell death in tumor cells overexpressing c-Met protein or expressing constitutively activated c-Met protein. c-Met, a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis.

Cedazuridine is a specific cytidine deaminase (CDA) inhibitor that was approved in combination with decitabine for the treatment of variable forms of myelodysplastic syndrome (MDS). It is known that decitabine is rapidly metabolized by CDA prior to reaching systemic circulation when administered orally. Thus, cedazuridine by inhibition of CDA increases systemic exposure of decitabine.

Pemigatinib, an oral kinases inhibitor, was approved under the brand name PEMAZYRE for the treatment of adults with previously treated, unresectable locally advanced, or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion. The FDA-approved indication for pemigatinib was granted under accelerated approval based on the overall response rate and duration of response in pre-marketing clinical trials. The drug inhibited FGFR1-3 phosphorylation and signaling and decreased cell viability in cancer cell lines with activating FGFR amplification and fusions that resulted in constitutive activation of FGFR signaling.

Blu-285 is a potent and selective inhibitor for hematologic malignancies with KIT Exon 17 Mutations. BLU-285 has demonstrated biochemical in vitro activity on the KIT exon-17 mutant enzyme, KIT D816V. Cellular activity of BLU-285 on KIT D816 mutants was measured by autophosphorylation in the human mast cell leukemia cell line HMC1.2, and the P815 mouse mastocytoma cell line with IC50= 4 and 22 nM, respectively. In vivo BLU-285 was well tolerated and has demonstrated dose-dependent antitumor efficacy. Complete tumor growth inhibition and ≥ 75% KIT kinase inhibition was observed with 10 mg/kg once daily, oral dosing of BLU-285 in the aggressive KIT exon 17 mutant driven P815 mastocytoma model grown as a solid tumor allograft as well as in a disseminated model of the disease. BLU-285 was also well tolerated in this in vivo model and had no adverse effects on body weight at either dose.

Tazemetostat (EPZ-6438) is a selective inhibitor of histone-lysine N-methyltransferase EZH2. The drug is under clinical development (phase II) for the treatment of Diffuse Large B Cell Lymphoma, Malignant Mesothelioma and Synovial Sarcoma.

TUCATINIB (ONT-380 or ARRY-380) is an orally active, reversible and selective small-molecule HER2 inhibitor invented by Array and licensed to Cascadian Therapeutics (previously named Oncothyreon) for development, manufacturing and commercialization. HER2, a growth factor receptor that is over-expressed in multiple cancers, including breast, ovarian, and stomach cancer. HER2 mediates cell growth, differentiation and survival, and tumors that overexpress HER2 are more aggressive and historically have been associated with poorer overall survival compared with HER2-negative cancers. ONT-380 is highly active as a single agent and in combination with both chemotherapy and Herceptin® (trastuzumab) in xenograft models of HER2+ breast cancer, including models of CNS metastases that were refractory to Tykerb® (lapatinib) or neratinib treatment. In a Phase 1 single agent clinical study, ONT-380 administered orally twice a day was well tolerated and demonstrated anti-tumor activity in heavily pre-treated HER2+ breast cancer patients with metastatic disease. Based on the strength of these preclinical and clinical trials, ONT-380 is advancing in one Phase 2 and three Phase 1b combination trials in patients with metastatic breast cancer. A second study reported the CNS activity of ONT-380 in combination with either T-DM1 or trastuzumab or capecitabine. Patients with brain metastases assessable for response were included in the combined analysis. Responses and clinical benefit in the CNS were reported with the three combinations tested, supporting future development of the drug for this particular indication.

Setmelanotide (RM-493), is an investigational, first-in-class melanocortin-4 receptor (MC4R) agonist in development for the treatment of rare genetic disorders of obesity. Setmelanotide is thought to activate the MC4R, part of a key biological pathway in humans that regulates weight by increasing energy expenditure and reducing appetite. Variants in genes within the MC4 pathway are associated with unrelenting hunger, known as hyperphagia, and severe, early-onset obesity. Setmelanotide is a potential replacement therapy that may restore lost activity in the MC4 pathway, reestablishing weight and appetite control in patients with these rare genetic disorders.

Osilodrostat (INN, USAN) (developmental code name LCI-699) is an orally active, non-steroidal corticosteroid biosynthesis inhibitor which is under development by Novartis for the treatment of Cushing's syndrome and pituitary ACTH hypersecretion (a specific subtype of Cushing's syndrome). Osilodrostat specifically acts as a potent and selective inhibitor of aldosterone synthase (CYP11B2) and at higher dosages of 11β-hydroxylase (CYP11B1). Osilodrostat decreases plasma and urinary aldosterone levels and rapidly corrects hypokalemia, in patients with primary aldosteronism and hypertension. At doses ≥1 mg o.d. Osilodrostat markedly increases 11-deoxycortisol plasma levels and blunts ACTH-stimulated cortisol release in ≈20% of patients, consistent with the inhibition of CYP11B1. In patients with resistant hypertension, Osilodrostat produces a non-significant reduction in blood pressure, possibly due to the increase in 11-deoxycortisol levels and the stimulation of the hypothalamic-pituitary-adrenal feedback axis. Because of the lack of selectivity, poor antihypertensive effect, and short half-life, the development of Osilodrostat as antihypertensive was halted. As of 2017, Osilodrostat is in phase III and phase II clinical trials for the treatment of pituitary ACTH hypersecretion and Cushing's syndrome, respectively.