Targeted protein degradation (TPD) is an emerging drug discovery approach with potential profound effect on drug discovery by providing opportunities toward drugging undruggable targets. The TPD paradigm includes two main approaches of differing molecular design that generate small molecules with a similar proteasome-dependent mechanism of action, namely, proteolysis targeting chimeras (PROTACs) and molecular glues (MGs). MGs are small molecules capable of binding to an E3 ligase and altering its surface and specificity, leading to the recruitment, ubiquitination, and subsequent degradation of substrates that are normally not targeted by the ligase (neosubstrates). PROTACs are larger bifunctional molecules with two ligands connected by a linker rationally designed to bring the desired target protein in close proximity to E3 ubiquitin ligase and induce its proteasomal degradation.<br/>This paper will discuss the development of a TPD platform at St Jude’s Children Research Hospital focusing on pediatric cancers, including Acute leukemia (AL), one of the leading causes of cancer-related death in children. Design of novel cereblon binders will be described, as well as their application in the development of PROTACs that potently degrade therapeutic targets such as BRD4, JAK2, and Lck in vitro and in vivo. The design of a Molecular Glue Library (MGL) containing over 5,000 small molecules, its screening against a large panel of cancer cell lines, and discovery of highly potent and selective GSPT1 and CK1a degraders will also be discussed. Extensive in vitro/vivo data will be disclosed to highlight lessons learned and discuss future opportunities for pediatric cancer research.

Developing PROTACs and molecular glues for pediatric leukemias

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