INCB-039110 (also known as Itacitinib) is an orally bioavailable inhibitor of Janus-associated kinase 1 (JAK1) with potential antineoplastic activity patented by Incyte Corporation for treatment of autoimmune disorders and cancer. Upon oral administration of NCB-039110, this agent selectively inhibits the phosphorylation and activity of JAK1, which may result in inhibition of JAK1-mediated signaling, induction of apoptosis, and reduction of cell proliferation in JAK1-expressing tumor cells. INCB-039110 in combination with nab-paclitaxel plus gemcitabine demonstrated an acceptable safety profile with clinical activity seen in patients with advanced solid tumors including pancreatic cancers. Based on the potential for additive or synergistic effects, NCB-039110 is currently being explored in combination with immunotherapeutic agents including the anti-programmed cell death protein 1 antibody and small molecule inhibitors.

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.

AT-9283 was being developed by Astex Pharmaceuticals as a treatment for cancer and myelofibrosis. AT-9283 is an inhibitor of mitosis (cell division) and is the second most progressed drug candidate in the Astex portfolio of novel molecularly targeted cancer drugs. All of Astex’s current products have been discovered internally using its proprietary drug discovery approach. AT9283 is a potent inhibitor of the Aurora A and B kinases and has been shown to arrest tumour growth in a range of tumour models. Aurora kinases play a key role in mitotic checkpoint control in cell division. Both Aurora A and B are over-expressed in many human tumours and are believed to be excellent targets for anti-cancer therapy.

HCI-2084 (wider known as TP-0903) is developing by Tolero Pharmaceuticals for the treatment of different cancers. HCI-2084 is a small molecule AXL receptor tyrosine kinase (RTK) inhibitor. AXL is involved in maintaining a mesenchymal phenotype in cancer cells that enhanced cell survival in stressed environments, and increased resistance to targeted therapies compared to epithelial cells. AXL overexpression has been observed in multiple tumor types that have acquired resistance to various agents. TP-0903 is participating in phase I/II clinical trial in patients with previously treated chronic lymphocytic leukemia (CLL). This study will investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of TP-0903. Besides, phase I is currently being conducted in patients with advanced solid tumors in the presence of TP-0903. In addition, TP-0903 was investigated in neuroblastoma (NB) cells, where this drug makes NB cells more vulnerable to the conventional chemotherapeutics.

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.

Novartis Oncology (previously Novartis) is developing nazartinib (formerly EGF 816), a third generation mutant-selective tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), for the treatment of solid malignancies, with a focus on non-small cell lung cancer. Nazartinib is a covalent mutant-selective EGFR inhibitor, with Ki and Kinact of 31 nM and 0.222 min−1 on EGFR(L858R/790M) mutant, respectively. Upon oral administration, nazartinib covalently binds to and inhibits the activity of mutant forms of EGFR, including the T790M EGFR mutant, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. EGF816 preferentially inhibits mutated forms of EGFR including T790M, a secondarily acquired resistance mutation, and may have therapeutic benefits in tumors with T790M-mediated resistance when compared to other EGFR tyrosine kinase inhibitors. As this agent is selective towards mutant forms of EGFR, its toxicity profile may be reduced as compared to non-selective EGFR inhibitors which also inhibit wild-type EGFR.

Naquotinib (ASP8273) is an orally available, irreversible, mutant-selective, epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Naquotinib was found by mass spectrometry to covalently bind to a mutant EGFR (L858R/ T790M) via cysteine residue 797 in the kinase domain of EGFR with long-lasting inhibition of EGFR phosphorylation for 24 h. In the NSCLC cell lines harboring the above EGFR mutations, Naquotinib had IC50 values of 8-33 nM toward EGFR mutants, more potently than that of WT EGFR (IC50 value of 230 nM). In mouse xenograft models, Naquotinib induced complete regression of the tumors after 14 days of treatment. ASP8273 even showed activity in mutant EGFR cell line which is resistant to other EGFR TKIs. Naquotinib is in phase III clinical trials for the oral treatment of EGFR mutated non-small cell lung cancer (NSCLC).

Flumatinib (HHGV678) is an orally bioavailable antineoplastic tyrosine kinase inhibitor. Flumatinib inhibits the wild-type forms of Bcr-Abl, platelet-derived growth factor receptor (PDGFR) and mast/stem cell growth factor receptor (SCFR; c-Kit) and forms of these proteins with certain point mutations. Flumatinib was extensively metabolized after oral administration, and the major metabolic pathways observed were amide hydrolysis, demethylation, oxidation, and glucuronide conjugation. It is in phase III clinical trials for the treatment of Chronic myeloid leukemia (in China).