The Use of Virtual Screening in ALK5 Kinase Inhibitor Discovery and Validation of Orally Active ALK5 Kinase Inhibitors in Oncology

The multifunctional cytokine, TGF-β, is often overexpressed in human tumors and in preclinical studies has been demonstrated to have autocrine and paracrine protumor activities including immune evasion, invasiveness, epithelial to mesenchymal transition, angiogenesis, tumor-stromal interactions, survival, induction of tumor interstitial pressure, and decreased drug penetration. These findings suggest that antagonism of the TGF-β pathway may be of benefit in the treatment of cancer. One attractive target, the type I TGF-β receptor (ALK5) has an intracellular serine/threonine kinase, which is required for TGF-β signaling and is amenable to inhibition by small molecule, ATP binding site-targeted kinase inhibitors. We utilized the growing understanding of the interactions between kinases and their ATP binding site inhibitors to pursue a number of focused lead discovery strategies. In one of those, we developed a novel shape-based pharmacophore model and discovered a potent, selective ALK5 inhibitor, HTS466284. ALK5 inhibitors obtained from several focused lead discovery strategies were optimized for oral bioavailability and in vivo activity resulting in the development of orally active ALK5 inhibitors such as SM16, which show potent antitumor activity in rodent tumor models.