Design and synthesis of antagonists of HOX-PBX protein-protein interaction
One of the most important and challenging new frontiers in Medicinal Chemistry is to develop strategies for discovering drugs that inhibit specific protein-protein interactions. These interactions are utilized in a wide range of biochemical processes, including many involved in human disease. In the current project we utilized a well-established protein-protein interaction (HOX-PBX/DNA), one that is known to play critical roles in both normal and diseased tissues, to demonstrate a structure-based design and focused small library strategy for producing compounds capable of inhibiting protein-protein interactions. Using the recently disclosed X-ray crystal structure of HOXB1-PBX1/DNA complex and molecular modeling studies as a guide, six scaffolds were designed to inhibit the transcription factor HOX-PBX/DNA complex and five of them were successfully synthesized and tested as antagonists of the HOX-PBX/DNA complex. In this dissertation, a total 82 compounds were prepared and tested as inhibitors of HOXA1-PBX1/DNA complex, which has the same binding interface as HOXB1-PBX1/DNA. The first small molecule antagonists of HOX-PBX protein-protein interactions were discovered. The most significant result from this project is the identification of the antagonist of HOX-PBX/DNA complex ( DH-HP-0052 ) with an IC 50 of 65 ± 15 μM. This compound is more potent than the much larger wild-type HOX-A1 peptide antagonist AQT FDWMK VKRN (IC 50 > 500 μM) when tested under the same high ionic strength conditions that stabilized the HOXA1-PBX1/DNA ternary complex. In addition, Compound DH-HP-0008 was found completely repressing BRN1/DNA binding. This compound provided a lead for the development of more potent BRN1 transcription complex antagonists.