TG101209 / Sanofi - LARVOL DELTA

Synthesis and biological assessment of BUB1B inhibitors for the treatment of clear cell renal cell carcinoma. (PubMed, Eur J Med Chem) - "Compound 8h demonstrated intracellular binding with BUB1B, similar to TG-101209, but through a different binding moiety that destabilizes the BUB1B protein structure, whereas TG-101209 stabilizes it. In conclusion, compound 8h, by destabilizing BUB1B and inducing apoptosis, shows promise as a potent therapeutic candidate for clear cell renal cell carcinoma (ccRCC) treatment."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • BUB1B

Targeting treatment resistance: unveiling the potential of RNA methylation regulators and TG-101,209 in pan-cancer neoadjuvant therapy. (PubMed, J Exp Clin Cancer Res) - "This study emphasizes the pivotal role of RMRs in pan-cancer neoadjuvant therapy, serving as predictive biomarkers for monitoring the tumor microenvironment, patient prognosis, and therapeutic response. Distinct molecular subtypes of RMRs aid individualized stratification in neoadjuvant therapy. Combining TG-101,209 adjuvant therapy presents a promising strategy to enhance the sensitivity of high-RMR-expressing tumors to chemotherapy and immunotherapy. However, further validation studies are necessary to fully understand the clinical utility of RNA methylation regulators and their impact on patient outcomes."

IO biomarker • Journal • Pan tumor • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

Design and evaluation of novel inhibitors for the treatment of clear cell renal cell carcinoma. (PubMed, Bioorg Chem) - "Here, we synthesized 27 new compounds that are derivatives of TG-101209 to modulate BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B)...Our study suggests that these compounds targeting BUB1B could offer a more effective and promising approach for ccRCC treatment compared to the conventionally used tyrosine kinase inhibitors. Our study underscores the potential of leveraging targeted therapies against specific molecular pathways in ccRCC may open new avenues for the development of effective treatment strategies against ccRCC."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • BUB1 • BUB1B

Pharmacologic screen identifies active combinations with BET inhibitors and LRRK2 as a novel putative target in lymphoma. (PubMed, EJHaem) - "The germinal center B-cell like diffuse large B-cell lymphoma (DLBCL) cell lines OCI-LY-19 and WSU-DLCL2 were exposed to 348 compounds given as single agents at two different concentrations and in combination with the BET inhibitor birabresib...The screening identified a series of compounds leading to a stronger antiproliferative activity when given in combination than as single agents: the histone deacetylase (HDAC) inhibitors panobinostat and dacinostat, the mTOR (mechanistic target of rapamycin) inhibitor everolimus, the ABL/SRC (ABL proto-oncogene/SRC proto oncogene) inhibitor dasatinib, the AKT1/2/3 inhibitor MK-2206, the JAK2 inhibitor TG101209...Genetic silencing demonstrated that LRRK2 sustains the proliferation of lymphoma cells, a finding paired with the association between high expression levels and inferior outcome in DLBCL patients. We identified combinations that can improve the response to BET inhibitors in lymphomas, and LRRK2 as a gene essential for..."

Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • AKT1 • SRC

Topical VX-509 Attenuates Psoriatic Inflammation Through the STAT3/FABP5 Pathway in Keratinocytes. (PubMed, Pharmacol Res) - "This study demonstrated administration of VX-509 is a potential promising topical drug for treatment of psoriasis, FABP5 is a critical targeted molecule in psoriasis therapy."

Journal • Dermatology • Immunology • Inflammation • Metabolic Disorders • Psoriasis • FABP5 • IL22 • STAT3

Cell proliferation effects of S-allyl-L-cysteine are associated with phosphorylation of janus kinase 2, insulin-like growth factor type-I receptor tyrosine kinase, and extracellular signal-regulated kinase 2 in primary cultures of adult rat hepatocytes. (PubMed, Eur J Pharmacol) - "Furthermore, the Janus kinase 2 (JAK2) inhibitor TG101209, phospholipase C (PLC) inhibitor U-73122, IGF-I receptor tyrosine kinase (RTK) inhibitor AG538, PI3 kinase inhibitor LY294002, MEK inhibitor PD98059, and mTOR inhibitor rapamycin completely suppressed the SAC-induced hepatocyte proliferation. SAC-induced IGF-I RTK (p95 kDa) and ERK2 (p42 kDa) phosphorylation had slower rises than JAK2, peaking at 20 and 30 min, respectively. These results indicate that SAC promoted cell proliferation by growth hormone receptor/JAK2/PLC pathway activation followed by activation of the IGF-I RTK/PI3K/ERK2/mTOR pathway in primary cultures of adult rat hepatocytes."

Journal • Preclinical • CCNB1 • FOS • IGF1 • JAK2 • MAPK1 • MYC • SEC23IP

S-Allyl-L-cysteine Promotes Cell Proliferation by Stimulating Growth Hormone Receptor/Janus Kinase 2/Phospholipase C Pathways and Promoting Insulin-Like Growth Factor Type-I Secretion in Primary Cultures of Adult Rat Hepatocytes. (PubMed, Biol Pharm Bull) - "The SAC-induced IGF-I secretion was completely suppressed by a selective Janus kinase 2 (JAK2) inhibitor (TG101209), a selective phospholipase C (PLC) inhibitor (U-73122), an intracellular Ca chelating agent (BAPTA-AM), and a granule secretion inhibitor (somatostatin)...Furthermore, binding of the monoclonal antibody against growth hormone (GH) to GH receptor was dose-dependently suppressed by SAC on immunofluorescence. These results showed that SAC promotes cell proliferation by stimulating GH receptor/JAK2/phospholipase C pathways and promoting autocrine secretion of IGF-I in primary cultures of adult rat hepatocytes."

Journal • Preclinical • IGF1 • JAK2

The JAK2 inhibitor TG101209 exhibits anti-tumor and chemotherapeutic sensitizing effects on Burkitt lymphoma cells by inhibiting the JAK2/STAT3/c-MYB signaling axis. (PubMed, Cell Death Discov) - "We also found that TG101209 displayed significant synergistic action and a sensitizing effect on the anti-Burkitt lymphoma activity of doxorubicin. The mechanistic study indicated that TG101209, by suppressing the JAK2/STAT3/c-MYB signaling axis and crosstalk between the downstream signaling pathways, plays an antilymphoma role. These data suggested that TG101209 may be a promising agent or alternative choice for the treatment of BL."

Journal • Burkitt Lymphoma • Hematological Malignancies • Lymphoma • Oncology

SWIM domain protein ZSWIM4 is required for JAK2 inhibition resistance in breast cancer. (PubMed, Life Sci) - "Our data implicated that ZSWIM4 might be an inducible resistance gene of JAK2 inhibition in breast cancer cells. The combination of JAK2 inhibitor and VDR inhibitor may achieve better coordinated therapeutic effect in breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor

Growth Hormone Signaling Pathway Leading to the Induction of DNA Synthesis and Proliferation in Primary Cultured Hepatocytes of Adult Rats. (PubMed, J Pharm Pharm Sci) - "The proliferative action of GH is mediated by two main signaling pathways. One includes activation of the GH receptor/JAK2/PLC/Ca2+ pathway, and the other involves activation of the p95-kDa IGF-I RTK/PI3K/ERK2/mTOR pathway in primary cultures of adult rat hepatocytes."

Journal • IGF1 • MAPK1

Identification of novel OTX015-containing combinations for lymphoma treatment (AACR 2018) - "Besides HDAC and mTOR inhibitors, in accordance with what previously reported (Boi, Gaudio, Bonetti et al, Clinical Cancer Res 2015), the ABL/SRC inhibitor dasatinib, the AKT1/2/3 inhibitor MK-2206, the JAK2 inhibitor TG101209 and the LRRK2 inhibitor LRRK2-IN appeared interesting combination partners. Experiments in additional cell lines and assessing the effects on the apoptosis are on-going and will be presented.Conclusion. A chemical screening has identified novel OTX015-containing combinations active in lymphoma cell lines that are worth of further investigations.Work supported by a San Salvatore Foundation grant."

Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Indolent Lymphoma • Mantle Cell Lymphoma

Autocrine secretion of insulin-like growth factor-I mediates growth hormone-stimulated DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. (PubMed, Eur J Pharmacol) - "Autocrine secretion of IGF-I into the culture medium was inhibited by a growth-inhibitory dose of TG101209, U-73122, somatostatin, or BAPTA/AM. These data indicate that the proliferative mechanism of action of GH is mediated mainly through a GH receptor/JAK2/PLC-stimulated increase in the autocrine secretion of IGF-I by primary cultured hepatocytes, followed by stimulation of the 95 kDa IGF-I receptor tyrosine kinase signaling pathway."

Journal • IGF1

Combination of JAK2 and HSP90 inhibitors: an effective therapeutic option in drug-resistant chronic myelogenous leukemia. (PubMed) - Genes Cancer - "When administered in mice bearing 32Dp210 T315I leukemia, combinational therapy using Ruxolitinib and AUY922 prolonged the survival significantly. Thus, a combination of JAK2 and HSP90 inhibitors could be a powerful strategy for the treatment of CML, especially in IM-resistant patients."

Journal • Biosimilar • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation. (PubMed, Cancers (Basel)) - "PAK1 physically interacts with Janus Kinase 2 (JAK2), and JAK2 inhibitor (TG101209) treatment inhibits mammosphere formation and reduces the nuclear PAK1 protein level...PAK1 inactivation inhibits CSC formation by decreasing pStat3 and extracellular IL-6 levels. Our results reveal that JAK2/PAK1 dysregulation inhibits the Stat3 signaling pathway and CSC formation, the PAK1/Stat3 complex regulates IL-6 gene expression, PAK1/Stat3 signaling regulates CSC formation, and PAK1 may be an important target for treating breast cancer."

Cancer stem cells • Journal