WP1066

WP1066, an analogue of AG490, is a novel and potent inhibitor of janus kinase 2 (JAK2), which inhibits the phosphorylation of JAK2 and degrades JAK2 protein consequently blocking JAK2’s downstream signal transducer and activator of transcription (transcription-3 and transcription-5) as well as phosphoinositide-3-kinase pathways in a dose- and time-dependent manner. Results of preliminary studies suggest that WP1066 inhibits the growth of xenograft tumors generated from Caki-1 renal carcinoma cells (RCC) suppressing tumor angiogenesis and exhibits antiproliferative activity in AML colony-forming cells from newly diagnosed AML patients as well as in AML cell lines OCIM2 and K562, which potentiates it to treat RCC, acute myeloid leukemia (AML) and other hematologic maglignancies.

Reference

Srdan Verstovsek, Taghi Manshouri, Alfonso Quintas-Cardama, David Harris, Jorge Cortes, Francis J. Giles, Hagop Kantarjian, Waldemar Priebe, and Zeev Estrov. WP1066, a novel JAK2 inhibitor, suppresses proliferation and induces apoptosis in erythroid human cells carrying the JAK2 V617F mutation. Clin Cancer Res 2008; 14: 788-796

Alessandra Ferrajoli, Stefan Faderl, Quin Van, Patricia Koch, David Harris, Zhiming Liu, Inbal Hazan-Halevy, Yongtao Wang, Hagop M. Kantarjian, Waldemar Priebe, and Zeev Estrov. WP1066 disrupts janus kinase-2 and induces caspase-dependent apoptosis in acute myelogenous leukemia cells. Cancer Res 2007; 67: 11291-11299

A Horiguchi, T Asano, K Kuroda, A Sato, J Asakuma, K Ito, M Hayakawa, M Sumitomo and T Asano.  STAT3 inhibitor WP1066 as a novel therapeutic agent for renal cell carcinoma. British Journal of Cancer 2010; 102: 1592-1599

The STAT3 inhibitor WP1066 synergizes with vorinostat to induce apoptosis of mantle cell lymphoma cells.[Pubmed:26116769]

Biochem Biophys Res Commun. 2015 Aug 14;464(1):292-8.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t (11; 14) (q13; q32). Drug resistance remains a formidable obstacle to treatment and the median survival for MCL patients is between 3 and 5 years. Thus, there is an urgent need to discover novel approaches to MCL therapy. The signal transducer and activation of transcription 3 (STAT3) has been found to be constitutively activated in several subtypes of MCL cell lines and MCL tumors. WP1066, a small-molecule inhibitor of STAT3, exerted antitumor activity in hematological and solid malignancies by inhibiting key survival and growth signaling pathways. In the present study, we evaluated the antiproliferative and proapoptotic activity of WP1066 combined with pan-histone deacetylase (HDAC) inhibitor vorinostat (SAHA) in a panel of MCL cell lines. In addition, potential mechanisms involved were also explored. The outcome showed that combination of WP1066 with SAHA resulted in synergistic growth inhibition and apoptosis induction in MCL cell lines in vitro. Furthermore, combination of WP1066 with SAHA inhibited the constitutive STAT3 activation and modulated mRNA expressions of anti- and pro-apoptotic genes. Our findings suggest that agents targeting the STAT3 pathway such as WP1066 may be useful therapeutic drugs for MCL when combined with SAHA.

WP1066 exhibits antitumor efficacy in nasaltype natural killer/T-cell lymphoma cells through downregulation of the STAT3 signaling pathway.[Pubmed:27633398]

Oncol Rep. 2016 Nov;36(5):2868-2874.

Nasal-type natural killer/T-cell lymphoma (nasal NKTCL) is an aggressive hematological neoplasm with poor prognosis, and its incidence is higher in Asia than in Western countries. Increasing evidence suggests that aberrant activation of signal transducers and activators of transcription 3 (STAT3) is related to numerous malignancies. However, the involvement of STAT3 in the pathogenesis of nasal NKTCL is poorly understood. In this study, immunohistochemistry (IHC) showed that 21/28 (75.0%) nasal NKTCL tissues harbored constitutively expression of phosphoSTAT3 (pSTAT3) which was positively correlated with the Ki67 levels (P0.05). Immunofluorescence (IF) also detected pSTAT3 expression in SNK6 cells (NKTCL cell line). Furthermore, WP1066 (a novel selective STAT3 inhibitor) was able to inhibit proliferation and induce apoptosis of SNK6 cells. Moreover, western blot analysis and RTPCR demonstrated that WP1066 downregulated the protein and mRNA expressions of the prosurvival molecules (including cMyc, cyclin D1, and Bcl2) in SNK6 cells. These results suggested that STAT3 activation represents a potential target in nasal NKTCL. WP1066 may be a promising agent in antitumor therapy against nasal NKTCL.

Delayed Administration of WP1066, an STAT3 Inhibitor, Ameliorates Radiation-Induced Lung Injury in Mice.[Pubmed:26563331]

Lung. 2016 Feb;194(1):67-74.

PURPOSE: The present study was designed to investigate the effects of WP1066, a specific inhibitor of STAT3 signaling, on radiation-induced lung injury in mice. METHODS: C57BL/6J mice were subjected to a single thoracic irradiation of 15 Gy X-ray and WP1066 was administrated through intraperitoneal injection. The early and delayed treatment groups were treated with WP1066 during the first 2 weeks and the second 2 weeks, respectively. The therapeutic effects of WP1066 were evaluated by survival analysis, histological examination, and measurement of inflammatory parameters and collagen deposition. The activation of STAT3 pathway was also estimated by immunohistochemical staining and Western blotting. RESULTS: Delayed treatment of WP1066, but not early treatment, prolonged survival time and prevented the development of radiation pneumonitis and the subsequent lung fibrosis in mice. WP1066 treatment also significantly suppressed the activation of STAT3 signaling in the irradiated lung tissues. CONCLUSIONS: The activation of STAT3 pathway might play an important part in the pathogenesis of radiation-induced lung injury. The protective effects of delayed treatment of WP1066 suggested STAT3 signaling could be a therapeutic target for radiation pneumonitis.

WP1066 suppresses macrophage cell death induced by inflammasome agonists independently of its inhibitory effect on STAT3.[Pubmed:28035720]

Cancer Sci. 2017 Mar;108(3):520-527.

The compound WP1066 was originally synthesized by modifying the structure of AG490, which inhibits the activation of signal transducer and activator of transcription 3 (STAT3) by directly targeting Janus kinases (JAKs). WP1066 exhibits stronger anti-cancer activity than AG490 against malignant glioma and other cancer cells and is regarded as a promising therapeutic agent. By screening a small library of target-known compounds, we identified WP1066 as an inhibitor of macrophage cell death induced by agonists of the NLRP3 inflammasome, an intracellular protein complex required for the processing of the proinflammatory cytokine interleukin (IL)-1beta. WP1066 strongly inhibited cell death as well as extracellular release of IL-1beta induced by inflammasome agonists in mouse peritoneal exudate cells and human leukemia monocytic THP-1 cells that were differentiated into macrophagic cells by treatment with PMA. However, inflammasome agonists did not increase STAT3 phosphorylation, and another JAK inhibitor, ruxolitinib, did not inhibit cell death, although it strongly inhibited basal STAT3 phosphorylation. Thus, WP1066 appears to suppress macrophage cell death independently of its inhibitory effect on STAT3. In contrast, WP1066 itself induced the death of undifferentiated THP-1 cells, suggesting that WP1066 differentially modulates cell death in a context-dependent manner. Consistent with previous findings, WP1066 induced the death of human glioma A172 and T98G cells. However, neither ruxolitinib nor AG490, the former of which completely suppressed STAT3 phosphorylation, induced the death of these glioma cells. These results suggest that WP1066 targets cell death-modulating molecules other than those involved in JAK-STAT3 signaling.