CYT387

CYT387, an aminopyrimidine derivative discovered by high-throughput enzyme and cell-based screening along with the optimization using structure-guided medicinal chemistry, is a potent and selective inhibitor of janus kinase 1 (JAK1), janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2) with values of 50% inhibition concentration IC₅₀ of 11 nM, 18 nM, 155 nM and 17 nM respectively. Recent studies have revealed that CYT387, at low nanomolar concentrations ranging between 500 and 1500 nM, is able to inhibit JAK2 signaling pathway, suppress proliferation and induce apoptosis in JAK2-dependent hematopoietic cell lines with non-hematopoietic cell lines intact.

Reference

Tyner JW, Bumm TG, Deininger J, Wood L, Aichberger KJ, Loriaux MM, Druker BJ, Burns CJ, Fantino E, Deininger MW. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010;115(25):5232-5240.

Liquid chromatography-tandem mass spectrometric assay for the JAK2 inhibitor CYT387 in plasma.[Pubmed:22476054]

J Chromatogr B Analyt Technol Biomed Life Sci. 2012 May 1;895-896:174-7.

A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for the JAK2 inhibitor CYT387 was developed and validated. Plasma samples were pre-treated using protein precipitation with acetonitrile containing cediranib as internal standard. The extract was directly injected into the chromatographic system after dilution with water. This system consisted of a sub-2 mum particle, trifunctional bonded octadecyl silica column with a gradient using 0.005% (v/v) of formic acid in a mixture of water and methanol. The eluate was transferred into the electrospray interface with positive ionization and the analyte was detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was validated in a 0.25-1000 ng/ml calibration range. Within day precisions were 3.0-13.5%, between day precisions 5.7% and 14.5%. Accuracies were between 96% and 113% for the whole calibration range. The drug was stable under all relevant analytical conditions. Finally, the assay was successfully used to assess drug levels in mice.

P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) restrict brain accumulation of the JAK1/2 inhibitor, CYT387.[Pubmed:23827160]

Pharmacol Res. 2013 Oct;76:9-16.

CYT387 is an orally bioavailable, small molecule inhibitor of Janus family of tyrosine kinases (JAK) 1 and 2. It is currently undergoing Phase I/II clinical trials for the treatment of myelofibrosis and myeloproliferative neoplasms. We aimed to establish whether the multidrug efflux transporters P-glycoprotein (P-gp; MDR1; ABCB1) and breast cancer resistance protein (BCRP;ABCG2) restrict oral availability and brain penetration of CYT387. In vitro, CYT387 was efficiently transported by both human MDR1 and BCRP, and very efficiently by mouse Bcrp1 and its transport could be inhibited by specific MDR1 inhibitor, zosuquidar and/or specific BCRP inhibitor, Ko143. CYT387 (10 mg/kg) was orally administered to wild-type (WT), Bcrp1(-/-), Mdr1a/1b(-/-) and Bcrp1;Mdr1a/1b(-/-) mice and plasma and brain concentrations were analyzed. Over 8h, systemic exposure of CYT387 was similar between all the strains, indicating that these transporters do not substantially limit oral availability of CYT387. Despite the similar systemic exposure, brain accumulation of CYT387 was increased 10.5- and 56-fold in the Bcrp1;Mdr1a/1b(-/-) mice compared to the WT strain at 2 and 8h after CYT387 administration, respectively. In single Bcrp1(-/-) mice, brain accumulation of CYT387 was more substantially increased than in Mdr1a/1b(-/-) mice, suggesting that CYT387 is a slightly better substrate of Bcrp1 than of Mdr1a at the blood-brain barrier. These results indicate a marked and additive role of Bcrp1 and Mdr1a/1b in restricting brain penetration of CYT387, potentially limiting efficacy of this compound against brain (micro) metastases positioned behind a functional blood-brain barrier.

Enhanced Antitumor Activity of Cetuximab in Combination with the Jak Inhibitor CYT387 against Non-Small-Cell Lung Cancer with Various Genotypes.[Pubmed:26685983]

Mol Pharm. 2016 Feb 1;13(2):689-97.

Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, is effective in the treatment of non-small-cell lung cancers (NSCLCs). However, resistance to EGFR inhibitors limits its effectiveness. In this study, we investigated the effectiveness of Jak-2 inhibitor, CYT387, in combination with cetuximab. Xenograft animal models were administered with cetuximab or CYT387 or their combination. It was observed that NSCLC cells exhibited enormous differences in responses to cetuximab; cell lines were more intrinsically resistant to cetuximab. In resistant cell lines (H1975 and H1650), the efficacy of cetuximab was increased when combined with CYT387, whereas CYT387 alone in low doses exhibited little effect on NSCLC cell proliferation. In addition, the antitumor activity of cetuximab was increased in H1975 resistant model in spite of low efficacy of cetuximab treatment alone in. Jak/STAT signaling was suppressed effectively by the combination of cetuximab and CYT387. In summary, our findings indicated that CYT387 has a potent indirect antitumor activity, and it is also synergistic in its activity in combination with cetuximab against NSCLC tumors, especially with cetuximab intrinsic-resistance tumors. These indications were mediated via Janus kinase (Jak)-signal transducer and transcription (STAT) pathway activator. Our results strongly and consistently supported the potential synergism of CYT387 as Jak inhibitor for anti-NSCLC therapy with EGFR-targeting agents.

Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis.[Pubmed:23459451]

Leukemia. 2013 Jun;27(6):1322-7.

JAK-STAT is a rational drug target in myelofibrosis (MF) given its association with JAK2/MPL mutations and aberrant inflammatory cytokine expression. We conducted a Phase 1/2 trial of CYT387, a potent JAK1/2 inhibitor, in patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia MF. Pre-planned safety and efficacy analysis has been completed for the initial 60 patients. In the dose-escalation phase (n=21), the maximum-tolerated dose was 300 mg/day based on reversible grade 3 headache and asymptomatic hyperlipasemia. Twenty-one and 18 additional patients were accrued at two biologically effective doses, 300 mg/day and 150 mg/day, respectively. Anemia and spleen responses, per International Working Group criteria, were 59% and 48%, respectively. Among 33 patients who were red cell-transfused in the month prior to study entry, 70% achieved a minimum 12-week period without transfusions (range 4.7->18.3 months). Most patients experienced constitutional symptoms improvement. Grade 3/4 adverse reactions included thrombocytopenia (32%), hyperlipasemia (5%), elevated liver transaminases (3%) and headache (3%). New-onset treatment-related peripheral neuropathy was observed in 22% of patients (sensory symptoms, grade 1). CYT387 is well tolerated and produces significant anemia, spleen and symptom responses in MF patients. Plasma cytokine and gene expression studies suggested a broad anticytokine drug effect.

Momelotinib (CYT387) is an ATP-competitive inhibitor of JAK1/JAK2 with IC50a of 11 nM and 18 nM,respectively. CYT387 shows much less activity against JAK3.

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