R428 (BGB324) is an inhibitor of Axl with IC50 of 14 nM. R428 was originated in Rigel Pharmaceuticals and was licensed to BerGenBio, which initiated clinical trials for the treatment of non-small cell lung cancer, metastatic melanoma and acute myeloid leukaemia.

PF-06747775 is an irreversible pyrrolopyrimidine inhibitor of epidermal growth factor receptor (EGFR) T790M mutants which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. The third-generation class of EGFR tyrosine kinase inhibitors PF-06747775 is a clinical candidate drug for treatment of non-small-cell lung cancer (NSCLC) driven by mutant EGFR.

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.

Bryostatin 1 is a macrocyclic lactone which can be isolated from the marine bryozoan, Bugula neritina. The effects of bryostatin 1 are attributed to its ability to selectively modulate the activity of two of the three subgroups of protein kinase C (PKC) isozymes. PKC isozymes are divided into three subgroups which differ in their molecular structures and co-factor requirements: classical PKC (cPKC), novel PKC (nPKC), and atypical PKC (aPKC). Bryostatin-1 modulates nPKC activity independent of a Ca2+ signaling. It activates cPKC only when associated with Ca2+ signaling. And, aPKC activity is not sensitive to bryostatin-1 administration. Ca2+ signals play an important role in synaptic transmission and information processing which creates a biological environment where Bryostatin-1 possesses a unique action profile. Bryostatin-1 will not affect cPKC activity in neurons which are not functioning as an active part of the signaling processing circuit with significant Ca2+influx and intracellular Ca2+ release. Bryostatin 1 is in phase II clinical trials for investigation as an anticancer agent; specifically for treatment of metastatic or recurrent head and neck cancer, ovarian epithelial cancer that has not responded to previous chemotherapy, and myelodysplastic syndrome. Bryostatin 1 has also generated interest as an investigational compound for the treatment of Alzheimer's disease.

NSI-189 is a novel oral drug which was developed by Neuralstem for the treatment of cognitive disorders. Now the drug is being tested in phase II of clinical trials in patients suffering from major depressive disorder. The mechanism of NSI-189 action is explained by its ability to stimulate the generation of new neurons in the hippocampus, however the exact target molecule is still unknown.

TG-100115 is a potent dual inhibitor of PI3K-gamma and PI3K-delta. TG-100115 has broad anti-inflammatory activities. TG-100115 provided potent cardioprotection, reducing infarct development and preserving myocardial function. In murine models of asthma and acute stages of chronic obstructive pulmonary disease, aerosolized TG100-115 demonstrated not only markedly inhibited anti-inflammatory activity but also, in the case of the asthma model, improved functional outcome for the test animals. TG-100115 can be used as a potent TRPM7 kinase inhibitor and a potent inhibitor of breast cancer cell migration.

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.

Cipargamin is an experimental synthetic antimalarial molecule belonging to the spiroindolone class. It possesses both the potency (average IC50 of 550 pM against asexual blood-stage P. falciparum) and favorable pharmacokinetics (elimination half-life of ~24 hours in humans) needed for a single-dose cure, a feature that could help slow the onset of parasite resistance and that is not shared by existing, approved antimalarial drugs. KAE609 is also unique in its ability to block transmission to mosquitoes. Cipargamin is a parasite P-type ATPase4 inhibitor. Cipargamin in phase II clinical trials for the treatment of acute, uncomplicated malaria due to plasmodium falciparum monoinfection. Nausea was the most common reported adverse effect. The adverse events were generally mild and did not lead to any discontinuations of the drug.

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.

LY-3039478 is an orally bioavailable, novel small molecule inhibitor of Notch signaling pathway, developed Eli Lilly and Company for cancer treatment. The Notch receptor, on the surfaces of progenitor cells and cancer cells, binds neighboring cell-surface ligands DLL or JAGGED. On ligand binding, the intramembrane protease γ-secretase cleaves the Notch intracellular domain (NICD). LY-3039478 is an exquisitely potent inhibitor of Notch-1 intracellular domain (N1ICD) cleavage with an IC50 of ∼1nM in most of the tumor cell lines tested. LY3039478 also potently inhibits mutant Notch receptor activity. Treatment with a gamma-secretase inhibitor, LY3039478, significantly inhibited the growth of 2 CCRCC(Clear cell renal cell carcinoma) cell lines in a concentration-dependent manner. LY3039478 treatment also led to decreased expression of Myc and Cyclin A1, two genes that were part of the NOTCH driven proliferative signature in murine and human model systems. LY3039478 treatment also led to G0/G1 cell cycle arrest in CCRCC cells. In a xenograft tumor model, LY3039478 inhibited N1ICD cleavage and expression of Notch-regulated genes in the tumor microenvironment. The inhibition of Notch cleavage also resulted in the induction of apoptosis in a Notch-dependent xenograft model. In immunodeficient NSG mice xenografted with 769-P CCRCC cells, LY3039478 treatment resulted in significantly increased survival and delayed tumor growth in independent cohorts of mice demonstrating in vivo efficacy in CCRCC. LY3039478 is being investigated in a clinical trial in patients with T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma in combination with Dexamethasone.