Gavinostat is an orally bioavailable hydroxymate inhibitor of histone deacetylase (HDAC) with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. Gavinostat inhibits class I and class II HDACs, resulting in an accumulation of highly acetylated histones, followed by the induction of chromatin remodeling and an altered pattern of gene expression. At low, nonapoptotic concentrations, this agent inhibits the production of pro-inflammatory cytokines such as tumor necrosis factor- (TNF-), interleukin-1 (IL-1), IL-6 and interferon-gamma. It is currently in phase 2 trials for Myeloproliferative disorders, Polycythaemia vera and Phase III for Duchenne muscular dystrophy announced. In clinical trials of givinostat as a salvage therapy for advanced Hodgkin's lymphoma, the most common adverse reactions were fatigue, mild diarrhea or abdominal pain, moderate thrombocytopenia, and mild leukopenia.

X-396 (Ensartinib) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Ensartinib has demonstrated activity in ALK treatment naïve and previously treated patients and has a generally well tolerated safety profile. Ensartinib is currently in a global phase 3 trial in ALK positive non-small cell lung cancer (NSCLC) patients. The phase 1/2 clinical findings support the preclinical results that the use of ensartinib may result in favorable therapeutic outcomes in patients with ALK NSCLC, including patients with CNS metastases. In this study, ensartinib was generally well tolerated with the most common adverse event being a rash.

Vorasidenib (also known as AG 881) was developed as an isocitrate dehydrogenase (IDH) type 1 in the cytoplasm and type 2 in the mitochondria, with potential antineoplastic activity. It is known that IDH is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Isocitrate dehydrogenases 1 and 2 (IDH1/2) are homodimeric enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid cycle. Vorasidenib participated in phase I clinical trials in patients with advanced hematologic malignancies and in gliomas.

Vadadustat is an Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitor. Patients with chronic kidney disease (CKD) have reduced levels of erythropoietin (EPO) and iron in the body, which can result in decreased number of oxygen-carrying red blood cells (RBCs) (anemia). The deficiency in RBCs causes inadequate oxygen delivery to cells and tissues. Vadadustat simulates the hypoxia response pathway by stabilizing key regulatory proteins called HIFs. Under normal conditions, when sufficient oxygen is present, HIF proteins are targeted for degradation by HIF-PH to maintain homeostasis in RBC production. Under conditions of hypoxia, HIF-PH activity is reduced, resulting in HIF stabilization. Stable HIF moves to the nucleus, where it activates target genes that increase EPO synthesis, resulting in the production of new RBCs, and suppression of hepcidin to promote iron absorption and mobilization. Vadadustat is currently in the phase 3 stage of development for the treatment of anemia secondary to CKD.

AZD-5363, a novel pyrrolopyrimidine-derived compound, inhibits all AKT isoforms with a potency of <10nM, and inhibited phosphorylation of AKT substrates in cells with a potency of ~0.3 to 0.8µM. AZD5363 monotherapy inhibited the proliferation of 41/182 solid and hematologic tumour cell lines with a potency of <3µM and 25/182 with a potency of <1µM. By targeting AKT, the key node in the PIK3/AKT signaling network, AZD-5363 may be used as monotherapy or combination therapy for a variety of human cancers. There is significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD-5363, and between RAS mutations and resistance. In xenograft studies in vivo AZD-5363 significantly reduced phosphorylation of PRAS40, GSK3β and S6. Chronic oral dosing of AZD-5363 causes dose-dependent inhibition of the growth of xenografts derived from various tumor types and AZD-5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib and trastuzumab in breast cancer xenografts. Dose-response at oral doses of 50 to 150mg/kg twice daily continuous dosing and intermittent dosing in the range of 100 to 200mg/kg twice daily, 4 days on, 3 days off have led to efficacy. AZD-5363 is in phase II clinical studies for the treatment of breast cancer; gastric cancer; non-small cell lung cancer.

Momelotinib (CYT387) is an ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases. Momelotinib is developing by Gilead Sciences for the oral treatment of pancreatic and non-small cell lung cancers, and myeloproliferative disorders (including myelofibrosis, essential thrombocythaemia and polycythaemia vera).

Quizartinib (AC220) is an orally bioavailable, small molecule receptor tyrosine kinase inhibitor that is being developed by Daiichi Sankyo Company (previously Ambit Biosciences) and Astellas Pharma as a treatment for acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and advanced solid tumours. The highest affinity target identified for Quizartinib was FLT3. The only other kinases with binding constants within 10-fold that for FLT3 were the closely related receptor tyrosine kinases KIT, PDGFRA, PDGFRB, RET, and CSF1R. Kinase inhibition of (mutant) KIT, PDGFR and FLT3 isoforms by quizartinib leads to potent inhibition of cellular proliferation and induction of apoptosis in in vitro leukemia models as well as in native leukemia blasts treated ex vivo.

Sotagliflozin (LX4211) is an orally-delivered small molecule compound that is currently in development for the treatment of type 1 and type 2 diabetes mellitus. Sotagliflozin (LX4211) inhibits both sodium-glucose cotransporter type 2, or SGLT2, a transporter responsible for most of the glucose reabsorption performed by the kidney, and sodium-glucose cotransporter type 1, or SGLT1, a transporter responsible for glucose and galactose absorption in the gastrointestinal tract, and to a lesser extent than SGLT2, glucose reabsorption in the kidney. Combining SGLT1 and SGLT2 inhibition in a single molecule would provide complementary insulin-independent mechanisms to treat diabetes.