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.

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.

Ozanimod (previously known as RPC-1063) is a selective immune-inflammatory modulator of the G protein-coupled receptors sphingosine 1-phosphate 1 and 5, which are part of the sphingosine 1-phosphate (S1P) receptor family. Treatment with S1P receptor modulators interferes with S1P signaling and blocks the response of lymphocytes (a type of white blood cell) to exit signals from the lymph nodes, sequestering them within the nodes. The result is a downward modulation of circulating lymphocytes and anti-inflammatory activity by inhibiting cell migration to sites of inflammation. Ozanimod is currently in phase III clinical trials for the treatment of relapsing multiple sclerosis (RMS) and ulcerative colitis, and also in phase II clinical trials to determine whether it is effective in the treatment of Crohn's disease.

Selumetinib (AZD6244 or ARRY-142886) is a potent, selective, and ATP-uncompetitive inhibitor of Ras-Raf-mitogen-activated protein kinase kinase (MEK1/2). This inhibition can prevent ERK activation, disrupt downstream signal transduction, and inhibit cancer cell proliferation and survival. Selumetinib has shown tumour suppressive activity in multiple rodent models of human cancer including melanoma, pancreatic, colon, lung, and breast cancers. AstraZeneca is responsible for development and commercialization of selumetinib.

Tafamidis meglumine (Vyndaqel®, Pfizer) is a novel, first-in-class drug for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP), a rare neurodegenerative disorder characterized by progressive sensory, motor and autonomic impairment that is ultimately fatal. Pathogenic mutations in the transthyretin (TTR) protein lead to destabilization of its tetrameric structure and subsequent formation of amyloid aggregates. Tafamidis is a small-molecule inhibitor that binds selectively to TTR in human plasma and kinetically stabilizes the tetrameric structure of both wild-type TTR and a number of different mutants. Clinical trials indicate that tafamidis slows disease progression in patients with TTR-FAP and reduces the burden of disease, demonstrating improvement in small and large nerve fiber function, modified body mass index and lower extremity neurological examination. Tafamidis meglumine has been launched for TTR FAP in the EU, Japan, Argentina, Malta and Mexico, and is preregistration in the US for this indication.

Zanubrutinib (formerly known as BGB-3111) was developed by BeiGene as a small-molecule inhibitor of Bruton's tyrosine kinase (BTK). The drug forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion, thus Zanubrutinib inhibits malignant B-cell proliferation and reduces tumor growth. Zanubrutinib was granted accelerated approval by the FDA in November 2019 based on clinical trial results that demonstrated an 84% overall response rate from zanubrutinib therapy in patients with mantle cell lymphoma (MCL). On August 31, 2021, the Food and Drug Administration approved zanubrutinib for adult patients with Waldenström’s macroglobulinemia (WM).

GBT440 (previously GTx011) is a potent and direct drug for sickle cell treatment. In sickle cell anemia, abnormal hemoglobin molecules are formed, which causes problems for the flow of blood and oxygen through the body. GBT440 can selectively bind to hemoglobin, thereby increasing its affinity for oxygen. By inhibiting hemoglobin polymerization, it also prevents deformation of the red blood cells. GBT440, renamed Voxelotor, is thought to help prevent sickle cells blocking blood vessels, and therefore reduces pain (sickle cell crisis) experienced by patients. GBT440 is well absorbed following intravenous and oral administration, and quickly partitions into the red blood cell with a small part re‐distributed into the plasma. GBT440 was well tolerated in a randomized, placebo‐controlled, double blind, parallel group phase I/II study in healthy volunteers and sickle cell disease patients. Headache is the most reported adverse event related to the use of this drug, and no serious adverse events are known. A phase 3 clinical trial examining the efficacy and safety of the drug (compared to placebo) is planned to be completed in 2019. Voxelotor was also studied as a potential therapy for treatment of low oxygen levels in the blood of idiopathic pulmonary fibrosis patients, but this program was discontinued because of a lack of clinical benefits.