Biologic activity of the novel small molecule STAT3 inhibitor LLL12 against canine osteosarcoma cell lines

Couto, Jason I.; Bear, Misty D.; Lin, Jiayuh; Pennel, Michael; Kulp, Samuel K.; Kisseberth, William C.; London, Cheryl A.

doi:10.1186/1746-6148-8-244

Cited by 22 publications

(28 citation statements)

References 39 publications

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“…While a variety of small molecule and nucleic acid antisense inhibitors have been evaluated in the preclinical setting and in early-phase clinical trials, none have yet attained FDA approval. As previously discussed, we had developed another small molecule inhibitor of STAT3 (LLL12) that reduced proliferation, and induced apoptosis and cell cycle arrest of a variety of tumor cell lines [ 15 , 16 , 36 ]. However, this was found to have poor oral bioavailability and unfavorable PK.…”

Section: Discussionmentioning

confidence: 99%

Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma

Gardner

Roberts

et al. 2017

PLoS ONE

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BackgroundSTAT3 is a transcription factor involved in cytokine and receptor kinase signal transduction that is aberrantly activated in a variety of sarcomas, promoting metastasis and chemotherapy resistance. The purpose of this work was to develop and test a novel putative STAT3 inhibitor, LY5.Methods and findingsAn in silico fragment-based drug design strategy was used to create LY5, a small molecule inhibitor that blocks the STAT3 SH2 domain phosphotyrosine binding site, inhibiting homodimerization. LY5 was evaluated in vitro demonstrating good biologic activity against rhabdomyosarcoma, osteosarcoma and Ewing’s sarcoma cell lines at high nanomolar/low micromolar concentrations, as well as specific inhibition of STAT3 phosphorylation without effects on other STAT3 family members. LY5 exhibited excellent oral bioavailability in both mice and healthy dogs, and drug absorption was enhanced in the fasted state with tolerable dosing in mice at 40 mg/kg BID. However, RNAi-mediated knockdown of STAT3 did not phenocopy the biologic effects of LY5 in sarcoma cell lines. Moreover, concentrations needed to inhibit ex vivo metastasis growth using the PuMA assay were significantly higher than those needed to inhibit STAT3 phosphorylation in vitro. Lastly, LY5 treatment did not inhibit the growth of sarcoma xenografts or prevent pulmonary metastasis in mice.ConclusionsLY5 is a novel small molecule inhibitor that effectively inhibits STAT3 phosphorylation and cell proliferation at nanomolar concentrations. LY5 demonstrates good oral bioavailability in mice and dogs. However LY5 did not decrease tumor growth in xenograft mouse models and STAT3 knockdown did not induce concordant biologic effects. These data suggest that the anti-cancer effects of LY5 identified in vitro were not mediated through STAT3 inhibition.

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Section: Discussionmentioning

confidence: 99%

Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma

Gardner

Roberts

et al. 2017

PLoS ONE

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“…Several small molecule STAT3 inhibitors have been developed by modifying curcumin, and some have shown promising activity both in vitro and in mouse xenograft models [56,57,58]. Agents with biologic activity inhibiting STAT3-related cellular functions may have therapeutic potential in the treatment of malignant tumours [59] and possibly CRSwNP. Future work with STAT3 inhibitors has to define the therapeutic potential of these agents in CRSwNP in vitro and, maybe later, in vivo in more detail.…”

Section: Discussionmentioning

confidence: 99%

Increased Activation and Differentiated Localization of Native and Phosphorylated STAT3 in Nasal Polyps

Linke

Pries²,

Könnecke³

et al. 2013

Int Arch Allergy Immunol

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Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial disease; the underlying mechanisms of cell signalling are not fully understood. STAT3 (signal transducer and activator of transcription 3) is a phosphokinase and a key signalling molecule implicated in cell cycle regulation. We studied the distribution and expression of STAT3 to examine the role of STAT3 in the pathogenesis of CRSwNP. Methods: We investigated tissue samples of the nasal polyps and inferior turbinate of patients with CRSwNP as well as samples of the inferior turbinate of subjects without chronic sinusitis. The expression levels of STAT3 and its activated form pSTAT3 were analysed using Western blotting, protein array, DNA microarray and immunohistochemistry. Results: No significant differences were found in STAT3-mRNA levels between the samples of nasal polyps and inferior turbinates of the same patient. However, the amount of pSTAT3 was increased in the polyp tissue compared to the inferior turbinates from both CRSwNP patients and control subjects (p < 0.01), indicating an activation of STAT3 in polyps. We identified a varying distribution pattern of pSTAT3; pSTAT3 was primarily found in superficial epithelial cells but not in the basal layer of the epithelium of the turbinate, whereas pSTAT3 was located in all layers of the epithelium of the polyp and mostly noted in the basal layer. Conclusions: Our results of the activation and varying localisation of STAT3 and its phosphorylated form in nasal polyps suggest that pSTAT3 plays a crucial role in the proliferative development of nasal polyps.

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“…Consistent activation of STAT3 occurs in a large subset of human and canine osteosarcoma and osteosarcoma cell lines, but not in normal osteoblasts. Down-regulation of STAT3 expression or activity reduces proliferation and induces apoptosis in human and canine cell lines [127][128][129][130]. Additionally, human and canine osteosarcoma possess overlapping transcriptional profiles, further supporting the concept that these diseases are similar at the molecular level [131].…”

Section: Inhibition Of Stat3 and Stat5 In Companion Animals: Current mentioning

confidence: 69%

Companion Animals as Models for Inhibition of STAT3 and STAT5

Kieslinger

Swoboda

Kramer

et al. 2019

Cancers

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The use of transgenic mouse models has revolutionized the study of many human diseases. However, murine models are limited in their representation of spontaneously arising tumors and often lack key clinical signs and pathological changes. Thus, a closer representation of complex human diseases is of high therapeutic relevance. Given the high failure rate of drugs at the clinical trial phase (i.e., around 90%), there is a critical need for additional clinically relevant animal models. Companion animals like cats and dogs display chronic inflammatory or neoplastic diseases that closely resemble the human counterpart. Cat and dog patients can also be treated with clinically approved inhibitors or, if ethics and drug safety studies allow, pilot studies can be conducted using, e.g., inhibitors of the evolutionary conserved JAK-STAT pathway. The incidence by which different types of cancers occur in companion animals as well as mechanisms of disease are unique between humans and companion animals, where one can learn from each other. Taking advantage of this situation, existing inhibitors of known oncogenic STAT3/5 or JAK kinase signaling pathways can be studied in the context of rare human diseases, benefitting both, the development of drugs for human use and their application in veterinary medicine.

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Biologic activity of the novel small molecule STAT3 inhibitor LLL12 against canine osteosarcoma cell lines

Cited by 22 publications

References 39 publications

Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma

Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma

Increased Activation and Differentiated Localization of Native and Phosphorylated STAT3 in Nasal Polyps

Companion Animals as Models for Inhibition of STAT3 and STAT5

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