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.

AZD1480 is a novel agent that inhibits Janus-associated kinases 1 and 2 (JAK1 and JAK2). In phase I study, AZD1480 was administered as an oral QD or b.i.d. monotherapy to patients with advanced solid tumors at eight dose levels in the ranges of 10–70 mg QD and 20–45 mg b.i.d. using a standard 3 3 design. AZD1480 had fast absorption, fast elimination, and dose-dependent increase in exposure from 10 mg to 50 mg. Unusual toxicity profile and overall lack of clinical activity led to discontinuation of development of AZD1480.

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.

PF-06840003 is a highly selective orally bioavailable Indoleamine 2,3-dioxygenase-1 (IDO-1) inhibitor with a potent antineoplastic activity. PF-06840003 reversed IDO-1-induced T-cell anergy in vitro. In vivo, PF-06840003 reduced intratumoral kynurenine levels in mice by >80% and inhibited tumor growth in multiple preclinical syngeneic models in mice, in combination with immune checkpoint inhibitors. A Phase 1 study of PF-06840003 in patients with Malignant Gliomas is ongoing.

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.

Merestinib (LY2801653) is a small molecule that has been shown in vitro to be a reversible type II ATP-competitive slowoff inhibitor of MET tyrosine kinase with a dissociation constant (Ki) of 2 nM, a pharmacodynamic residence time (Koff) of 0.00132 min−1 and a half-life (t1/2) of 525 min. Preclinical testing also has shown merestinib to inhibit several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, NTRK1/2/3, and DDR1/2 and the serine/threonine kinases MKNK1/2. Merestinib is being investigated in a phase II clinical trials in patients with biliary tract cancer, non-small cell lung cancer and solid tumours.

Entospletinib (GS-9973) is an adenosine triphosphate competitive inhibitor of Syk that disrupts kinase activity, which is currently in clinical trials for multiple B-cell malignancies. The most common treatment-emergent serious adverse events included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia.

Vistusertib (AZ-2014) is a dual inhibitor of mTORC1/mTORC2 which was developed by AstraZeneca for the treatment of cancer. The drug is under clinical development (phase II) in patients with Renal Carcinoma, Squamous Non Small Cell Lung Cancer, Diffuse Large B-Cell Lymphoma, Meningioma, Breast cancer and Gastric cancer, either alone or in combination therapy. Vistusertib penetrates blood-brain barrier.