Design and Synthesis of Novel Menin PROTACs for Pediatric Leukemia
Introduction
Mixed lineage leukemia is a very aggressive blood cancer that predominantly occurs in pediatric patients and is characterized by the presence of MLL fusion proteins that are the result of chromosomal translocations affecting the MLL gene at 11q23. A critical component of MLL-fusion protein complex is a protein called Menin. Numerous studies have demonstrated a critical role of Menin as an oncogenic cofactor in leukemic transformations mediated by MLL fusion proteins. MI-503 is a small molecule inhibitor that binds to Menin and inhibits its interaction with MLL-fusion proteins. MI-503 has been shown to be effective in mouse models of MLL leukemias. PROTACs or proteolysis targeting chimeras are compounds that target proteins for degradation by hijacking the activity of E3 ubiquitin ligases to promote degradation. PROTACs are particularly effective in cancers of the circulatory system and have the advantage over traditional therapeutics in that permanent occupancy of the targeted protein is not necessary as the PROTAC uses the in vivo degradation machinery to catalytically degrade proteins of interest. Our hypothesis is that the development of PROTACs targeting fusion proteins produced as a result of chromosomal rearrangements in pediatric tissues or their interacting proteins will provide compounds that can directly address the critical mutated proteins that drive the etiology of certain pediatric cancers and thus provide novel therapeutics for the treatment of pediatric cancers. Our goal is to identify linkers and E3 recruiting elements and develop medicinal chemistry approaches to develop PROTACS using the MI-503 small molecule.
Methods
We will build a library of small molecules that bind E3-ligases known to work in the PROTAC paradigm. In addition, we will acquire linkers of varying chemical properties, length and flexibility. Medicinal chemistry approaches for generating linker-E3 binding small molecules will be defined and pursued. Our first candidate “war head” for developing a functional PROTAC will be MI-503.
Results
We have successfully synthesized two novel PROTACs, CIDD-0160855 and CIDD-0160908, through a 25-26 steps synthesis. Both PROTACs were reacted under “Click” chemistry conditions with an azide that possess glycol linkers to the E3 ligands and tested for Menin binding.
Conclusion
Binding of our novel PROTACs to the target Menin was confirmed and a protein degradation assay is ongoing.