Galunisertib - CAS 700874-72-2
Catalog number:
Not Intended for Therapeutic Use. For research use only.
TGF-β Receptor
Galunisertib, also known as LY2157299, is a novel selective small molecule transforming growth factor beta receptor (TGF-βR) kinase inhibitor.LY2157299 inhibited HCC cell migration on Laminin-5, Fibronectin, Vitronectin, Fibrinogen and Collagen-I and de novo phosphorylation of pSMAD2. LY2157299 inhibited HCC migration and cell growth independently of the expression levels of TGF-βRII.
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white to off-white solid powder
LY-2157299; LY2157299; LY 2157299; Galunisertib
Current Developer:
Eli Lilly.
1.Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors.
Fujiwara Y1, Nokihara H2, Yamada Y3, Yamamoto N2, Sunami K2, Utsumi H2,4, Asou H5, TakahashI O5, Ogasawara K6, Gueorguieva I7, Tamura T2,8. Cancer Chemother Pharmacol. 2015 Dec;76(6):1143-52. doi: 10.1007/s00280-015-2895-4. Epub 2015 Nov 3.
PURPOSE: Inhibition of transforming growth factor-beta receptor I (TGF-beta RI)-mediated signaling pathways blocks tumor growth and metastases in nonclinical studies. Galunisertib (LY2157299), a small molecule inhibitor of TGF-beta RI serine/threonine kinase, had antitumor effects with acceptable safety/tolerability in a first-in-human dose (FHD) study conducted mainly in Caucasian patients with glioma. In this nonrandomized, open-label, dose-escalation study, we assessed safety/tolerability, pharmacokinetics (PK), and tumor response in Japanese patients.
2.A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma.
Brandes AA1, Carpentier AF1, Kesari S1, Sepulveda-Sanchez JM1, Wheeler HR1, Chinot O1, Cher L1, Steinbach JP1, Capper D1, Specenier P1, Rodon J1, Cleverly A1, Smith C1, Gueorguieva I1, Miles C1, Guba SC1, Desaiah D1, Lahn MM1, Wick W1. Neuro Oncol. 2016 Feb 21. pii: now009. [Epub ahead of print]
BACKGROUND: The combination of galunisertib, a transforming growth factor (TGF)-β receptor (R)1 kinase inhibitor, and lomustine was found to have antitumor activity in murine models of glioblastoma.
3.Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway.
Herbertz S1, Sawyer JS2, Stauber AJ2, Gueorguieva I3, Driscoll KE4, Estrem ST2, Cleverly AL3, Desaiah D2, Guba SC2, Benhadji KA2, Slapak CA2, Lahn MM2. Drug Des Devel Ther. 2015 Aug 10;9:4479-99. doi: 10.2147/DDDT.S86621. eCollection 2015.
Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development.
4.Effects of TGF-beta signalling inhibition with galunisertib (LY2157299) in hepatocellular carcinoma models and in ex vivo whole tumor tissue samples from patients.
Serova M1,2, Tijeras-Raballand A1,2, Dos Santos C1,2, Albuquerque M3, Paradis V3, Neuzillet C2, Benhadji KA4, Raymond E2, Faivre S2,3, de Gramont A1,2. Oncotarget. 2015 Aug 28;6(25):21614-27.
Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-β receptor (TβR)-I activation currently under clinical investigation in hepatocellular carcinoma (HCC) patients. Our study explored the effects of galunisertib in vitro in HCC cell lines and ex vivo on patient samples. Galunisertib was evaluated in HepG2, Hep3B, Huh7, JHH6 and SK-HEP1 cells as well as in SK-HEP1-derived cells tolerant to sorafenib (SK-Sora) and sunitinib (SK-Suni). Exogenous stimulation of all HCC cell lines with TGF-β yielded downstream activation of p-Smad2 and p-Smad3 that was potently inhibited with galunisertib treatment at micromolar concentrations. Despite limited antiproliferative effects, galunisertib yielded potent anti-invasive properties. Tumor slices from 13 patients with HCC surgically resected were exposed ex vivo to 1 µM and 10 µM galunisertib, 5 µM sorafenib or a combination of both drugs for 48 hours. Galunisertib but not sorafenib decreased p-Smad2/3 downstream TGF-β signaling.
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