Galunisertib (700874-72-2) is a TGF-β kinase (ALK5) antagonist.1 It stimulated hematopoiesis from primary myelodysplastic syndrome bone marrow specimens via downregulation of SMAD2 phosphorylation.2 It has been in clinical trials for treatment of various cancers.3-5 Galunisertib has more recently been used to enhance the anti-neuroblastoma activity of anti-GD2 antibody Dinutuximab with natural killer cells6 and preserved the function of in vitro expanded natural killer cells in AML and colon cancer models7. Galunisertib reversed TGF-β and regulatory T cell mediated suppression of human T cell proliferation. In combination with PD-L1 blockade, it resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models.8
References/Citations:
1) Bueno et al. (2008), Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-β kinase antagonist, in mice; Eur. J. Cancer 44 142
2) Zhou et al. (2011), Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase; Cancer Res. 71 955
3) Rodon et al. (2015), First-in-human dose study of the novel transforming growth factor-b-receptor I kinase inhibitor LY2157299 monohydrate in patients with advances cancer and glioma; Clin. Cancer Res. 21 553
4) Herbertz et al. (2015), Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway; Drug Des. Devel. Ther. 9 4479
5) Brandes et al. (2016), A Phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma; Neuro. Oncol. 18 1146
6) Tran et al. (2017), TGFβR1 Blockade with Galunisertib (LY2157299 Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells; Clin. Cancer Res. 23 804
7) Otegbeye et al. (2018), Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models; PLoS One 13 e0197008
8) Holmgaard et al. (2018), Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete response, as monotherapy and in combination with checkpoint blockade; J. Immunother. Cancer 6 47
