The Transforming growth factor-beta (TGF beta) superfamily is a group of multipotent growth factors that control proliferation, quiescence and differentiation. Aberrant signal transduction and downstream target activation contribute to tumorigenesis and targeted therapy has therefore been considered a promising avenue. Using various modeling pipelines, we analyzed the structure-function relationship between ligand and receptor molecules of the TGF beta family. We further simulated the molecular docking of Galunisertib, a small molecule inhibitor targeting TGF beta signaling in cancer, which is currently undergoing FDA-approved clinical trials. We found that proprotein dimers of Activin isoforms differ at intrachain disulfide bonds, which support prior evidence of varying pro-domain stability and isoform preference. Further, mature proteins possess flexibility around conserved cystine knots to functionally interact with receptors or regulatory molecules in similar but distinct ways to TGF beta. We show that all Activin isoforms are capable of assuming a closed- or open-dimer state, revealing structural promiscuity of their open forms for receptor binding. We propose the first structural landscape for Activin receptor complexes containing a type I receptor (ACVR1B), which shares a pre-helix extension with TGF beta type I receptor (TGF beta R1). Here, we artificially demonstrate that Activin can bind TGF beta R1 in a TGF beta-like manner and that TGF beta 1 can form signaling complexes with ACVR1B. Interestingly, Galunisertib was found to form stable inhibitory structures within the homologous kinase domains of both TGF beta R1 and ACVR1B, thus halting receptor-promiscuous signaling. Overall, these observations highlight the challenges of specific TGF beta cascade targeting in the context of cancer therapies.