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.

Sodium artesunate, an artemisinin derivative, is used in malaria treatment. Artesunate, has been licensed in Thailand for the treatment of falciparum malaria since 1990. It is a potent antimalarial drug that can reduce parasitaemia by 90% within 24 h of administration. Sodium artesunate was first isolated in China, it is a water soluble antimalaria used clinically in China.

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.

Nifurtimox is a nitrofuran derivative used as a primary agent in the treatment of American trypanosomiasis (Chagas' disease) caused by Trypanosoma cruzi, especially in the acute, early stage of the disease. The efficacy of nifurtimox in the treatment of chronic Chagas' disease varies from one country to another, possibly due to variation in the sensitivity of different strains of the organism. Nifurtimox has also been used to treat African trypanosomiasis (sleeping sickness) and is active in the second stage of the disease (central nervous system involvement). When nifurtimox is given on its own, about half of all patients will relapse, but the combination of melarsoprol with nifurtimox appears to be efficacious. Nifurtimox forms a nitro-anion radical metabolite that reacts with nucleic acids of the parasite causing significant break down of DNA. Nifurtimox undergoes reduction and creates oxygen radicals such as superoxide. These radicals are toxic to T. cruzi. Mammalian cells are protected by the presence of catalase, glutathione, peroxidases, and superoxide dismutase. Accumulation of hydrogen peroxide to cytotoxic levels results in parasite death. Side effects occur following chronic administration, particularly in elderly people. Major toxicities include immediate hypersensitivities such as anaphylaxis and delayed hypersensitivity reaction involving icterus and dermatitis. Central nervous system disturbances and peripheral neuropathy may also occur.

Lonafarnib is a well-characterized, late-stage, orally active inhibitor of farnesyl transferase, an enzyme involved in modification of proteins through a process called prenylation. It is Investigated for use/treatment in Progeria, Cancer, Hepatitis D. Lonafarnib completely inhibits Rheb prenylation and phosphorylation of S6 ribosomal protein in cell culture, indicating a lack of alternative Rheb prenylation. Other groups have demonstrated that inhibition of protein synthesis via inactivation of eukaryotic elongation factor (eEF2) could be an alternate mechanism of lonafarnib induced growth inhibition that is independent of RAS/p70S6K eEF. Adverse effects included fatigue, diarrhea, dyspnea and neutropenia and respiratory insufficiency.

Lurbinectedin (PM-01183) - is a synthetic tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one alkaloid analogue with potential antineoplastic activity. Lurbinectedin covalently binds to residues lying in the minor groove of DNA, which may result in delayed progression through S phase, cell cycle arrest in the G2/M phase and cell death. Lurbinectedin is a novel anticancer agent currently undergoing late-stage (Phase II /III) clinical evaluation in platinum-resistant ovarian, BRCA1/2-mutated breast and small-cell lung cancer. Lurbinectedin is structurally related to trabectedin and it inhibits active transcription and the DNA repair machinery in tumour cells.

Opicapone (Ongentys®), a potent, oral, third-generation, long-acting, peripheral catechol-O-methyltransferase (COMT) inhibitor, is approved as the adjunctive treatment to levodopa (L-Dopa)/dopa-decarboxylase inhibitor (DDCI) therapy in adults with Parkinson's disease (PD) and end-of-dose motor fluctuations who cannot be stabilized on those combinations. Opicapone is a hydrophilic 1,2,4-oxadiazole analog with a pyridine N-oxide at position 3, with these modifications enhancing its potency and extending its duration of action, whilst avoiding cell toxicity. In preclinical animal studies, Opicapone-induced inhibition of peripheral (but not central) COMT activity was associated with a prolonged increase in systemic and central exposure to L-Dopa, with a corresponding reduction in 3-OMD exposure. Following single or multiple doses of Opicapone (5–1200 mg) in healthy adult volunteers or patients with PD, Opicapone inhibited COMT activity in ex vivo erythrocyte assays in a reversible dose-dependent manner, with the duration of Opicapone-induced COMT inhibition independent of dose. Adjunctive Opicapone was generally well tolerated during more than a year of treatment in BIPARK I and BIPARK II (double-blind plus extension phases). The recommended dosage is 50 mg once daily, which should be taken at bedtime at least 1 h before or after L-Dopa combinations.

Bempedoic acid (also known as ETC-1002) is a novel investigational drug being developed for the treatment of dyslipidemia, hypercholesterolemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid β-oxidation. Investigations into the mechanism of action revealed that bempedoic acid-free acid activates AMP-activated protein kinase in a Ca(2+)/calmodulin-dependent kinase β-independent and liver kinase β-1-dependent manner, without detectable changes in adenylate energy charge. In the liver, bempedoic acid is also converted to a coenzyme A (CoA) derivative (ETC-1002-CoA )which directly inhibits ATP citrate lyase (ACL), a key enzyme that supplies a substrate for cholesterol and fatty acid synthesis in the liver. Inhibition of ACL by ETC-1002-CoA results in reduced cholesterol synthesis and upregulation of LDL receptor activity in the liver. This promotes the removal of LDL-C from the blood.