The biological importance of disordered proteins (IDPs) is well recognized but knowledge of how disorder mediates IDP function is incomplete. We investigate the potential use of a prototypical IDP, namely p27, as a target for oncological therapies as it is one of the most frequently misregulated proteins in human cancers. p27 is a cyclin E or A/cyclin-dependent kinase 2 inhibitor whose expression is regulated by several transcriptional, translational and post-translational events. However, p27 can be functionally inactivated by oncogenic mechanisms, either by proteosomal degradation or by mislocalization to the cytoplasm. Given the role of p27 in human cancers, designing small molecules for pharmaceutical intervention of p27 is of utmost importance.An essential first step in this process is to identify how p27 interacts with small molecules. Since IDPs such as p27 are highly flexible, their full conformational range is not observable by any one structure determination technique. In this talk, we use long time-scale simulations and machine learning techniques to probe quantitatively how the conformational landscape of p27 is altered as a consequence of small molecule interactions. We show that small molecules potentially contract the conformational space accessed by apo-p27. Further, we also show that the response of p27 to different classes of small molecules is unique, leading to exquisite and often precise interactions that are mediated by hydrophobic interactions. We conclude with an outline of current challenges in targeting disordered proteins.