Doramapimod (BIRB-796) is a p38 MAPK inhibitor, relatively potent against alpha isoform. Oral doramapimod exerts anti-inflammatory potential in humans in vivo. Doramapimod has entered clinical trials for the treatment of autoimmune diseases.

Dilmapimod is a potent p38 mitogen-activated protein kinase (MAPK) inhibitor. It was investigated for its anti-inflammatory effect in non-head injury trauma patients at risk for developing acute respiratory distress syndrome. IL-1β was identified as a gene regulated by dilmapimod that could influence c-reactive protein levels. Dilmapimod had been in phase III clinical trials by GlaxoSmithKline for the treatment of rheumatoid arthritis, neuropathic pain, coronary artery disease (CAD) and chronic obstructive pulmonary disease (COPD). However, these studies were discontinued.

7-Hydroxystaurosporine (UCN-01) is a protein kinase inhibitor which is under development as an anti-cancer agent in the USA and Japan. Although UCN-01 was originally isolated from the culture broth of Streptomyces sp. as a protein kinase C-selective inhibitor, its ultimate target as an anti-cancer agent remains elusive. As a single agent, UCN-01 exhibits two key biochemical effects, namely accumulation of cells in the G1 phase of the cell cycle and induction of apoptosis. Both these effects may be important for its anti-cancer activity. As a modulator, 7-Hydroxystaurosporine enhances the cytotoxicity of other anti-cancer drugs such as DNA-damaging agents and anti-metabolite drugs through putative abrogation of G2 and/or S phase accumulation induced by these anti-cancer agents. 7-Hydroxystaurosporine had been in phase II clinical trials Life Sciences for the treatment of T-cell lymphoma, malignant melanoma, pancreatic cancer, small cell lung cancer, acute myeloid leukemia, ovarian cancer. However, the research was either discontinued or suspended.

Losmapimod (GW856553, GSK-AHAB) is a selective, potent, and orally active p38 MAPK (p38α and p38β isoforms) inhibitor that acts by competing for the kinase ATP binding site. GlaxoSmithKline (GSK) is developing oral losmapimod for the treatment of acute coronary syndromes (phase III), chronic obstructive pulmonary disease (phase II) and primary focal segmental glomerulosclerosis (phase II). Oral losmapimod was in phase II development for the treatment of rheumatoid arthritis and major depressive disorder; however, it appears that development for these indications has been discontinued. No further development was reported for atherosclerosis, dyslipidaemia and neuropathic pain.

Verosudil (AR-12286) is a selective Rho-kinase inhibitor for the treatment of glaucoma and ocular hypertension being developed by Aerie Pharmaceuticals in the US. Verosudil was in phase II/III clinical trials for the treatment of glaucoma and in phase II clinical trials for the treatment of ocular hypertension.

Selonsertib, also known as GS-4997, is a small-molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1), which promotes inflammation, apoptosis and fibrosis in settings of increased oxidative stress associated with NASH pathogenesis. GS-4997 prevents the production of inflammatory cytokines, down-regulates the expression of genes involved in fibrosis, suppresses excessive apoptosis and inhibits cellular proliferation. GS-4997 is currently being evaluated in an ongoing Phase 2 study in patients with NASH and moderate to severe liver fibrosis.

Famitinib, an orally active, small molecule, is a tyrosine kinase inhibitor against multiple targets, including vascular endothelial growth factor receptor 2/3, platelet-derived growth factor receptor, and stem cell factor receptor (c-kit). Jiangsu Hengrui Medicine Co is developing famitinib against a wide variety of advanced-stage solid cancers. Famitinib is participating in phase III clinical trials to evaluate its safety and efficacy in patients with advanced colorectal adenocarcinoma. The other phase III clinical trial for patients with non-squamous non-small cell lung cancer was terminated because of the difficulty in recruitment. In addition, the drug is involved in phase II clinical trials for the treatment of cervical cancer, endometrial cancer, fallopian tube cancer, gastrointestinal stromal tumors, nasopharyngeal cancer, and neuroendocrine tumors.

Crenolanib is an orally active, highly selective, small molecule, next generation inhibitor of platelet-derived growth factor receptor (PDGFR) tyrosine kinase. Crenolanib, manufactured by Arog Pharmaceuticals in Dallas, is taken orally with chemotherapy. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma. Crenolanib is an orally bioavailable, selective small molecule inhibitor of type III tyrosine kinases with nanomolar potencies against platelet-derived growth factor receptors (PDGFR) (isoforms PDGFRα and PDGFRβ) and Fms-related tyrosine kinase 3 (FLT3). Besides PDGFR and FLT3, crenolanib does not inhibit any other known receptor tyrosine kinase (RTK) (e.g. VEGFR and FGFR) or any other serine/threonine kinase (e.g., Abl, Raf) at clinically achievable concentrations. Preclinical trials have shown Crenolanib to be active in inhibiting both wild-type and mutant FLT3. Crenolanib is cytotoxic to the FLT3/ITD-expressing leukemia cell lines Molm14 and MV411, with IC50s of 7 nM and 8 nM, respectively. In immunoblots, crenolanib inhibited phosphorylation of both the wild-type FLT3 receptor (in SEMK2 cells) and the FLT3/ITD receptor (in Molm14 cells) in culture medium with IC50s of 1-3 nM. Importantly, the IC50 of crenolanib against the D835Y mutated form of FLT3 was 8.8 nM in culture medium. Furthermore, crenolanib had cytotoxic activity against primary samples that were obtained from patients who had developed D835 mutations while receiving FLT3 TKIs. In vitro, the IC50 of crenolanib for inhibition of FLT3/ITD in plasma was found to be 34 nM, indicating a relatively low degree of plasma protein binding. From pharmacokinetic studies of crenolanib in solid tumor patients, steady state trough plasma levels of roughly 500 nM were found to be safe and tolerable, suggesting that crenolanib could potentially inhibit the target in vivo. Crenolanib has no significant activity against c-KIT, which may be an advantage in that myelosuppression can be avoided.1Furthermore, there was no evidence of QTc prolongation in patients treated with crenolanib. In summary, crenolanib offers a number of advantages over other FLT3 TKIs. Clinical trials of crenolanib in AML patients with FLT3 activating mutations are being planned.