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.

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.

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.

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.

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.