TAK-715 (Takeda) was a p38 MAPK inhibitor that had been implicated in the pro-inflammatory cytokine signal pathway, the inhibitors of which are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Inhibition of p38 MAPK and LPS-stimulated release of TNF-α from human monocytic THP-1 cells by TAK-715 was demonstrated in vitro; its inhibition of LPS-induced TNF-α production was demonstrated in vivo in mice. TAK-715 had showed good bioavailability in mice and rats and efficacy in a rat adjuvant-induced arthritis model. It was advanced into clinical Phase II trials but was discontinued, as it did not satisfy criteria for further development.

VX-745 (Neflamapimod) is a brain-penetrant highly selective, orally bioavailable drug that inhibits the intracellular enzyme p38 mitogen-activated protein kinase alpha (MAPKa). It is currently in phase 2 clinical studies in patients with early Alzheimer's disease. The targeting of p38 MAPK by VX-745 was associated with the suppression of the release of inflammatory mediators, including interleukin (IL)-1β and tumor necrosis factor (TNF)α, known to be implicated in exacerbating the pathophysiology of rheumatoid arthritis (RA). The drug was in phase II of the clinical trial for RA, but that studies were discontinued.

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.

SAR407899 is a potent, ATP-competitive Rho kinase inhibitor. It antihypertensive action in animals. Sanofi is developing SAR 407899 for the treatment of microvascular angina (Syndrome X). It was previously being developed in clinical trials for the treatment of diabetic neuropathies, diabetic nephropathies, erectile dysfunction, pulmonary hypertension, hypertension and kidney disorders, but development was discontinued for those indications.

VX-970 (VE-822) is an ATR kinase inhibitor. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. Vertex Pharmaceuticals is developing VX 970 for the treatment of advanced solid tumours. Phase I/II development is underway in the US for small-cell lung cancer and in the UK for solid tumours. Phase II development of VX 970 as a combination therapy in urogenital cancer, ovarian, primary peritoneal and fallopian tube cancer indications is underway in the US.

Lestaurtinib (CEP-701, KT-5555) is an orally bio-available polyaromatic indolocarbazole alkaloid derived from K-252a. Lestaurtinib is a multi-targeted tyrosine kinase inhibitor which has been shown to potently inhibit FLT3 at nanomolar concentrations in preclinical studies, leading to its rapid development as a potential targeted agent for treatment of AML. Phase I studies have shown lestaturtinib to be an active agent particularly when used in combination with cytotoxic drugs. Currently, Phase II and Phase III studies are underway aiming to establish the future of this agent as a treatment option for patients with FLT3-ITD AML.

Filgotinib (GLPG0634) is a highly selective JAK1 inhibitor. GLPG0634 is a promising drug candidate for the future treatment of autoimmune and inflammatory disorders. It is in phase III clinical trials (initiated mid-2016) for the treatment of rheumatoid arthritis, Crohn's disease and ulcerative colitis. Most common adverse events observed were infections, gastrointestinal disorders and nervous system disorders.

XL019 is a potent and selective JAK2 inhibitor. XL019 shows 50-fold or greater selectivity for JAK2, versus a panel of over 100 serine/threonine and tyrosine kinases, including other members of the JAK family. XL019 is non-selective for JAK2V617F or wild-type JAK2 and potently inhibits STAT3 and STAT5 phosphorylation in cells harboring either JAK2V617F or wild-type JAK2. Unfortunately, XL019 treatment was associated with the unexpected occurrence of neurotoxicity. Phase I clinical trials have been terminated.

BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. Bristol-Myers Squibb was developing BMS 690514, as an oral treatment for cancer. BMS-690514 had being in phase II for the treatment of breast cancer; non-small cell lung cancer, but later these studies were discontinued.

CGM-097, a novel, highly optimized, and selective inhibitor of the p53-Mdm2 interaction. CGM-097 binds to human Mdm2 protein with a Ki value of 1.3 nM, activates p53 in human cells and induces robust p53-dependent cell cycle arrest and apoptosis in human p53 wild-type tumor cells. Its activity and selectivity has been tested and confirmed across a large panel of cancer cell lines from the Cancer Cell Line Encyclopedia. CGM-097 displays desirable pharmacokinetic and pharmacodynamic profiles in animals together with excellent oral bioavailability, which triggers rapid and sustained activation of p53-dependent pharmacodynamic biomarkers resulting in tumor regression in multiple xenografted models of p53 wild-type human cancer. The validation and understanding of its mechanism of action, the overall favorable drug-like properties and the characterization of its on-target toxicological profile in preclinical species strongly supported the initiation of Phase I clinical trials with CGM-097 in pre-selected patients with p53 wild-type tumors.