Design, Synthesis And Screening Of The TGF-β Receptor ALK5 Inhibitors

The multifunctional cytokine transforming growth factor β (TGF- β )is a member of a large family of growth factors involved in the regulation of a diverse array of biological processes including cell growth, differentiation, cell adhesion, migration, extracellular matrix (ECM) deposition, and immune response regulation.The pathological activation of the transforming growth factor p pathway plays an important role in the progression of tissue fibrotic diseases in major organs and also enhances tumor invasiveness and matastasis. Due to its central role in TGF-P signaling, the TGF-P Type I receptor (TβRI, ALK5) is emerging as an exciting target for blockade of the TGF-P pathway.In this paper, we first built a docking-derived model of ALK5/SB-431542 complex using the FlexX docking program. On the basis of analysis of the possible binding mode of ALK5/SB-431542 complex, three series of novel compounds as 2,4,5-trisubstituted-l H-pyrazoline-5-ons,1,5- disubstitutedpyrazoles-3-carboxamide and l,5-disubstitutedpyrazoles-3-hydroxymethyl were designed and synthesized. All the compounds were identified by ~1H-NMR and MSThe ALK5 inhibitory activities were evaluated with a cell based luciferase reporter gene. The primary biological tests showed that most of the compounds exhibited certain ALK5 inhibitory activity at concentration of 1μM and 0.1μM and three compounds displayed moderate ALK5 inhibitory activity. In the toxicity test by MTT method, nearly all compounds revealed lower toxicity compared to the positive compound.Based on the docking model of ALK5/SB-431542 complex and the SAR results deduced from our synthetic compounds, we outlined the binding model of SB-431542 to the ATP site of ALK5, which could guide the next step of design and synthesis of ALK5 inhibitors.