AZD-3759 is an oral inhibitor of both wild-type and mutant EGFR with IC50 values in nanomolar range. The drug was discovered by AstraZeneca for the treatment of non-small-cell lung cancer with CNS metastases. AZD-3759 can penetrate the blood-brain barrier and was confirmed to be effective in vitro with NSCLC cell lines as well as in mouse model of brain metastases. AZD-3759 is currently in Phase 1 clinical trial.

VTP-27999 is an alkyl amine renin inhibitor. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans. Vitae Pharmaceuticals was developing VTP 27999 for the treatment of chronic kidney disease. VTP 27999 was in phase I clinical development in the US. However, the product is no more on the company pipeline and it appears that the development has been discontinued.

GSK-2256294 is a potent, reversible, tight binding inhibitor of isolated recombinant human sEH (soluble epoxide hydrolase) (IC50 = 27 pM; t1/2 = 121 min) and displays potent inhibition against the rat (IC50 = 61 pM) and murine (IC50 = 189 pM) orthologs of sEH. GSK-2256294A also displays potent cellular inhibition (IC50 = 0.66 nM) of sEH in an assay developed using a cell line transfected with the human sEH enzyme. GSK-2256294 was well-tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD. GSK-2256294 is in phase I clinical trials for the treatment of COPD.

R1479 (4′-azidocytidine) is a specific inhibitor of hepatitis C virus (HCV) replication. 4′-azidocytidine triphosphate is an inhibitor of native HCV replicase and recombinant HCV polymerase (NS5B). Balapiravir (R1626) is the tri-isobutyrate ester prodrug of R1479 under clinical development to improve exposure of R1479 upon oral administration.

APR-246 is a methylated form of PRIMA-1, 2-hydroxymethyl-2-methoxymethyl-aza-bicyclo[2.2.2]octan-3-one (PRIMA-1MET). APR-246, is a prodrug that is converted to the Michael acceptor methylene quinuclidinone (MQ) that binds covalently to cysteines in p53, leading to refolding and restoration of wild type p53 function. MQ also targets the cellular redox balance by inhibiting thioredoxin reductase (TrxR1) and depleting glutathione. APR-246 can rescue mutant forms of the p53 family members p63 and p73 that share high sequence homology with p53. APR-246 has demonstrated compelling pre-clinical antitumor activity in a wide variety of solid and hematological (blood) tumors, including ovarian cancer, small cell lung cancer, esophageal cancer and acute myeloid leukemia (AML), among others. Furthermore, strong synergy has been seen with both traditional anticancer agents, such as chemotherapy, as well as newer mechanism-based anticancer drugs. A Phase I clinical study has been completed, demonstrating a favorable safety profile and both biological and clinical responses in hematological tumors with mutations in the p53 gene. A Phase Ib clinical study in combination with full dose chemotherapy (carboplatin and pegylated liposomal doxorubicin) has also been completed, demonstrating a favorable safety profile in patients with high-grade serous ovarian cancer (HGSOC). APR-246 is currently in a Phase II clinical trial in patients with HGSOC, and additional Phase Ib clinical studies of APR-246 in other cancer indications are planned.

Seletalisib (UCB-5857) is a potent, ATP-competitive, and selective phosphoinositide 3-kinase (PI3K) delta inhibitor. Findings from cellular assays of adaptive immunity demonstrated that seletalisib blocks human T-cell production of several cytokines from activated T-cells. Additionally, seletalisib inhibited B-cell proliferation and cytokine release. In human whole blood assays, seletalisib inhibited CD69 expression upon B-cell activation and anti-IgE-mediated basophil degranulation. Seletalisib safety, tolerability and pharmacokinetic/pharmacodynamic profiles support its continued clinical development in immune-inflammatory diseases. UCB Pharma is developing Seletalisib for the treatment of immune and inflammatory diseases including Activated PI3K delta Syndrome (APDS), Sjogren's syndrome and psoriasis.

Nastorazepide (Z-360) is a selective, orally available, gastrin/cholecystokinin 2 (CCK-2) receptor antagonist with potential antineoplastic activity. Z-360 binds to the gastrin/CCK-2 receptor, thereby preventing receptor activation by gastrin, a peptide hormone frequently associated with the proliferation of gastrointestinal and pancreatic tumor cells. It is currently under development as a therapeutic drug for pancreatic cancer, gastroesophageal reflux disease and peptic ulcers. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue.

PLX8394 is a potent and selective inhibitor of B-Raf V600E (IC50 14 nM for WT and 3.8 nM for V600E mutant). Unlike vermurafenib, sorafenib and dabrafenib, PLX8394 does not cause paradoxical MAPK pathway activation. PLX8394 is under investigation in phase I/II of clinical trial for the treatment patients with advanced unresectable solid tumors.

Seviteronel (VT-464) is a 17,20-lyase selective inhibitor of CYP17A1, which plays key roles in adrenal and intratumoral de novo biosynthesis of androgens. The inhibition of 17,20-lyase activity by seviteronel (VT-464) is enough to reduce androgen levels, and its preserving of 17alpha-hydroxylase activity largely avoids interference with the production of other steroidal hormones. Seviteronel (VT-464) also has shown AR-antagonist activity independent of CYP17 enzyme inhibition. It is currently in phase 2 clinical trials as a therapeutic for castration-resistant prostate cancer patients.

BI-224436 is an HIV-1 integrase inhibitor with effective antiviral activity that acts through a mechanism that is distinct from that of integrase strand transfer inhibitors (INSTIs). This 3-quinolineacetic acid derivative series was identified using an enzymatic integrase long terminal repeat (LTR) DNA 3'-processing assay. A combination of medicinal chemistry, parallel synthesis, and structure-guided drug design led to the identification of BI 224436 as a candidate for preclinical profiling. It has antiviral 50% effective concentrations (EC50s) of <15 nM against different HIV-1 laboratory strains and cellular cytotoxicity of >90 μM. BI-224436 also retains full antiviral activity against recombinant viruses encoding INSTI resistance substitutions N155S, Q148H, and E92Q. In drug combination studies performed in cellular antiviral assays, BI-224436 displays an additive effect in combination with most approved antiretrovirals, including INSTIs. BI-224436 has drug-like in vitro absorption, distribution, metabolism, and excretion (ADME) properties, including Caco-2 cell permeability, solubility, and low cytochrome P450 inhibition. It exhibited excellent pharmacokinetic profiles in rat (clearance as a percentage of hepatic flow [CL], 0.7%; bioavailability [F], 54%), monkey (CL, 23%; F, 82%), and dog (CL, 8%; F, 81%). Based on the excellent biological and pharmacokinetic profile, BI 224436 was advanced into phase 1 clinical trials. Trials with clinical candidate BI-224436 were put on hold despite promising results.