Drugs in Clinical Pipeline: Galunisertib

Galunisertib [4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-6-carboxamide] is an orally available, novel selective small molecule transforming growth factor beta receptor (TGF- βR) kinase inhibitor. TGF beta R1 kinase inhibitor that in vitro selectively blocks TGF beta signaling. Galunisertib selectively blocks transforming growth factor-β receptor I kinase and TGF-β signaling. LY2157299 H2O is being studied for the treatment of a variety of cancers, such as liver cancer and brain cancer. TGF beta promotes tumors growth, suppresses the immune system, and increases the ability of tumors to spread in the body. Immune function is suppressed in cancer patients, and TGF beta worsens immunosuppression by enhancing the activity of immune cells called T regulatory cells. TGF beta also reduces immune proteins, further decreasing immune activity in patients.

Galunisertib (pronounced gal ue" niser'tib) developed by Lilly's is currently under investigation as an oral treatment for advanced/metastatic malignancies, including Phase 2 evaluation in hepatocellular carcinoma, myelodysplastic syndromes (MDS), glioblastoma, and pancreatic cancer.

The activity of LY2157299 is as follows:

IC₅₀ (TβR1 enzyme assay) = 86 nM

IC₅₀ (TβR2 enzyme assay) = 2 nM

Common Name: Galunisertib

Synonyms:  LY-2157299; LY2157299; LY 2157299

IUPAC Name: 4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-6-carboxamide

CAS Number: 700874-72-2

SMILES: CC1=CC=CC(=N1)C2=NN3CCCC3=C2C4=C5C=C(C=CC5=NC=C4)C(=O)N

Mechanism of Action: Kinase Inhibitor; TGF-bR Inhibitor

Indication: Various Cancers; Anti-tumor Therapy

Development Stage: Phase II Trials

Company: Eli Lilly and Company, USA

Eidogen Sertanty Inc Provides Kinase Knowledge Base (KKB): a Collection of nearly 1.6 M Kinase Inhibitors.

The transforming growth factor beta or TGF-β signaling pathway plays a pleiotropic role in both normal and tumor tissues, including tumor-stroma interactions [1, 2]. The canonical TGF-β signaling pathway becomes activated when one of the three ligands (TGF-β1, TGF-β2, TGF-β3) binds to the TGF-β receptor II (TGF-βRII), which subsequently heterodimerizes with the TGF-β receptor I (TGF-βRI or ALK5) and transphosphorylates the kinase domains of both receptors. This phosphorylation step leads to a recruitment and phosphorylation of SMAD2 and SMAD3 (pSMAD2 and pSMAD3). Next, this complex initiates the canonical or SMAD-dependent signaling cascade leading to nuclear translocation and downstream gene transcription [3]. In addition to the canonical signaling pathway, other activation pathways (non-canonical pathways) have also been described [4]. The non-canonical or non-SMAD-dependent activation of the TGF-β pathway includes signaling via jun N-terminal kinase (JNK), p38 MAPK, ERK or MEKK.

In the past, several small molecule inhibitors targeting the TGF-βRI serine/threonine kinase activity have been developed, including LY2157299 monohydrate (galunisertib) [5], which has been found to inhibit pSMAD2 expression in different tumor models [6, 7]. Galunisertib is now being investigated in clinical trials and has very recently been shown to elicit anti-tumor effects in patients with glioblastoma or hepatocellular carcinoma [8, 9].

References:

1. Roberts, A. B.; et. al. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci U.S.A. 1981, 78(9), 5339-5343.

2. Akhurst, R. J.; et. al. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov 2012, 11(10), 790-811.

3. Heldin, C. H.; et. al. Role of Smads in TGFβ signaling. Cell Tissue Res. 2012, 347(1), 21-36.

4. Derynck, R.; et. al. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003, 425(6958), 577-584.

5. Lahn, M.; et. al. TGF-beta inhibitors for the treatment of cancer. Expert Opin Investig Drugs 2005, 14(6), 629-643.

6. Sawyer, J. S.; et. al. Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. Bioorg Med Chem Lett 2004, 14(13), 3581-3584.

7. Dituri, F.; et. al. Differential inhibition of the TGF-β signaling pathway in HCC cells using the small molecule inhibitor LY2157299 and the D10 monoclonal antibody against TGF-β receptor type II. PLoS ONE. 2013, 8(6), e67109.

8. Rodon, J.; et al. First-in-human dose study of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Canc Res 2015, 21(3), 553-560.

9. Faivre, S. J.; et. al. Randomized dose comparison phase II study of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate (LY) in patients with advanced hepatocellular carcinoma (HCC). ASCO Gastrointestinal Cancers Symposium, 2014.

10. Bueno, L.; et. al. Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-βkinase antagonist, in mice. Eur J Cancer 2008, 44(1), 142-150.

11. Workman, P. New cancer drugs in the horizon. Future Oncol 2005, 1(3), 315-318.

12. Mundla, S. R. TGF-Beta Inhibitors. US7872020B2; US2010120854A1.