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.

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.

BMS 911543 is a selective orally administered small molecule inhibitor of Janus kinase 2 (JAK2), developed by BristolMyers Squibb for the myelofibrosis treatment. BMS 911543 displayed potent antiproliferative effects in mutated JAK2expressing cell lines. A superior antiproliferative response occurred in primary progenitor cells isolated from patients with JAK2positive myeloproliferative disease (MPD) compared with those isolated from healthy volunteers. In vivo, a single oral dose of BMS 911543 resulted in durable JAK2phosphorylated STAT signalling pathway inhibition in multiple species. In a JAK2expressing xenograft model (SET2), BMS 911543 displayed a minimally effective dose of <2 mg/kg on phosphorylated STAT5 pathway inhibition.

NS-018 is a potent inhibitor of Janus kinase 2 (JAK2) enzyme activity and Src-family kinases. It was developed as an oral therapy for the treatment of myelofibrosis. Overall NS-018 has been used in trials studying the treatment of primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia. NS-018 is a highly active JAK2 inhibitor, with an IC50 of 0.72 nM, 46-, 54-, and 31-fold selectivity for JAK2 over JAK1 (IC50, 33 nM), JAK3 (IC50, 39 nM), and Tyk2 (IC50, 22 nM). NS-018 also inhibits Src-family kinases, especially SRC and FYN, and weakly inhibits ABL and FLT3 with 45- and 90-fold selectivity for JAK2, respectively. NS-018 shows potent inhibitory activity against cell lines JAK2V617F or MPLW515L mutations or the TEL-JAK2 fusion gene.

Decernotinib is an oral JAK3 kinase inhibitor developed by Vertex for the treatment of rheumatoid arthritis. Although the drug demonstrated a good potency in vitro and in phases I and II of clinical trials, its development was 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.