The efficacy of conventional chemotherapies in treating clear cell renal cell carcinoma (ccRCC) is often limited due to its high molecular diversity, generally low response rates to standard treatments, and prevalent drug resistance. Recent advancements in the molecular understanding of ccRCC, alongside the discovery of novel therapeutic agents targeting specific proteins, have significantly altered the treatment landscape for ccRCC. Here, we synthesized 27 new compounds that are derivatives of TG-101209 to modulate BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B). BUB1B has been recently identified as a drug target for the development of effective ccRCC treatment based on global transcriptomics profiling of ccRCC tumours and gene co-expression network analysis. We characterized the molecular structures of these 27 compounds by ¹H and ¹³C NMR and Mass spectrometry. We evaluated the effect of these 27 compounds by analysing the modulation of the BUB1B expression. Our primary objective was to design and assess the efficacy of these new compounds in reducing the viability of Caki-1 cells, a ccRCC cell line. We performed the computational docking studies by the Schrödinger Maestro software and demonstrated that three of these compounds (13a, 5i, and 5j) effectively downregulated BUB1B expression and eventually triggered necrosis and apoptosis in the Caki-1 cell line based on the structure-activity relationship (SAR) analysis. The IC50 values for compounds 13a, 5i, and 5j were calculated as 2.047 µM, 10.046 µM, and 6.985 µM, respectively, indicating their potent inhibitory effects on cell viability. 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.

01 Aug 2022·eJHaem

Pharmacologic screen identifies active combinations with BET inhibitors and LRRK2 as a novel putative target in lymphoma

Article

Author: Mascia, Michele ; Barreca, Marilia ; Arribas, Alberto J. ; Stathis, Anastasios ; Tarantelli, Chiara ; Bertoni, Francesco ; Sartori, Giulio ; Rinaldi, Andrea ; Napoli, Sara ; Gaudio, Eugenio ; Scalise, Lorenzo ; Spriano, Filippo ; Cascione, Luciano ; Golino, Gaetanina ; Zucca, Emanuele

AbstractInhibitors of the Bromo‐ and Extra‐Terminal domain (BET) family proteins have strong preclinical antitumor activity in multiple tumor models, including lymphomas. Limited single‐agent activity has been reported in the clinical setting. Here, we have performed a pharmacological screening to identify compounds that can increase the antitumor activity of BET inhibitors in lymphomas.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 combination partners included small molecules targeting important biologic pathways such as PI3K/AKT/MAPK signaling and apoptosis, approved anticancer agents, kinase inhibitors, epigenetic compounds. 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. The novel finding was the benefit given by the addition of the LRRK2 inhibitor LRRK2‐IN‐1, which was validated in vitro and in vivo. 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 lymphomas and as putative novel target for this type of tumors.

01 Jul 2022·European Journal of Pharmacology

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

Article

Author: Ogihara, Masahiko ; Kimura, Mitsutoshi ; Moteki, Hajime

The cell proliferation effect of S-allyl-L-cysteine (SAC) and its mechanisms were examined in primary cultures of adult rat hepatocytes. In serum-free cultivation, SAC (10^-6 M)-stimulated hepatocytes showed significant proliferation compared to control at 5-h culture; the effect was dependent on the culture time and the dose of SAC (EC₅₀ value 8.58 × 10^-8 M). In addition, SAC-stimulated hepatocytes significantly increased mRNA expression levels of c-Myc and c-Fos at 1 h and cyclin B1 at 3.5 and 4 h, respectively. In contrast, alliin and allicin, structural analogs of SAC, did not show these effects observed with SAC. The SAC-induced hepatocyte proliferation effects were completely suppressed by monoclonal antibodies against growth hormone receptor and insulin-like growth factor type-I (IGF-I) receptor, respectively. 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. JAK2 (p125 kDa) phosphorylation in cultured hepatocytes peaked 5 min after SAC stimulation. 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.

News (Medical) associated with TG-100948

30 Jul 2007

·www.biospace.com

TargeGen, Inc. Initiates Multi-Center Phase II Clinical Trial Of TG100801, a Topically Applied Kinase Inhibitor In Macular Degeneration Patients

SAN DIEGO, July 30 /PRNewswire/ -- TargeGen, Inc. today announced that the Company has initiated a multi-center Phase II clinical trial of topically applied TG100801 in patients with age-related macular degeneration (AMD). (Logo: ) AMD is the leading cause of blindness in adults with more than 3.5 million estimated patients worldwide. Currently approved treatments for macular degeneration require repeated injection into the eye and act primarily by reducing VEGF mediated retinal leakage. TG100801 is administered non-invasively as an eye drop and is designed to suppress VEGF mediated leakage and additional kinase targets associated with inflammation, edema, and angiogenesis which are the pathological hallmarks of AMD and other back of the eye diseases including diabetic macular edema and proliferative diabetic retinopathy. "The initiation of this trial is a significant milestone for TargeGen," stated Peter G. Ulrich, President, CEO and Co-Founder of TargeGen. "TG100801 is an important drug candidate that potentially addresses the leading causes of debilitating vision loss in adults in a more comprehensive way and may eliminate or reduce the requirement for repeated injections into the eye." In addition to TG100801, TargeGen is developing TG101348, an oral Jak2 inhibitor for the potential treatment of myeloproliferative diseases and TG100115, a PI3K inhibitor for the potential treatment of certain inflammatory disorders. A second topically applied compound for eye disease, TG100948, is in early development. About TargeGen, Inc. TargeGen, Inc. is a privately held vascular biology-focused biopharmaceutical company based in San Diego, CA. TargeGen primarily develops small molecule kinase inhibitors that target vascular leakage (edema), vascular proliferation (angiogenesis) and inflammation. Edema, angiogenesis and inflammation are involved in the pathology of many major human diseases. TargeGen initiated operations in 2002 and has raised capital from top tier venture capital sources. Current investors include VantagePoint Venture Partners, Forward Ventures, Enterprise Partners, Chicago Growth Partners, BB BIOTECH, Innovis Investments, H&Q Capital Management, Pappas Ventures and other investors. Photo: NewsCom: AP Archive: PRN Photo Desk, photodesk@prnewswire.comTargeGen, Inc. CONTACT: TargeGen, Inc., +1-858-678-0760, fax, +1-858-678-0160,info@targegen.com Web site:

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Indication	Highest Phase	Country/Location	Organization	Date
Choroidal Neovascularization	Preclinical	-	Sanofi	-
Diabetic macular oedema	Preclinical	-	Sanofi	-
Dystrophy, Macular	Preclinical	-	Sanofi	-
Myeloproliferative Disorders	Preclinical	-	Sanofi	-

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