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PROTAC Molecules for the Treatment of Autoimmune Disorders.

Targeting key drivers of disease for loss or degradation has drawn significant attention as a desirable outcome for numerous therapeutic treatments. Since its initial design by Sakamoto et al. in 2001, PROTAC (Proteolysis-Targeting Chimera) technology has been successfully applied in the development of heterobifunctional molecules that can promote target protein degradation and is often achieved indirectly by modulation of upstream signaling pathways, transcriptional programs, and/or epigenetic events. Early examples of compounds affecting degradation utilized small molecules or peptides to bridge interactions between a target protein with components of the ubiquitin proteasomal system (UPS). The UPS is pivotal in the regulation of almost all cellular processes such as apoptosis, DNA transcription and repair, immune response, inflammation, ion channels, and so forth. Recently, PROTAC molecules (also called SNIPER or degronomid) has been refined for efficacy and efficiency, comprising a heterobifunctional compound. Heterobifunctional PROTAC molecules generally consist of one end that recruits the E3 ligase complex and the other end that engages the target protein. When complexation occurs, the recruited E3 ligase complex ubiquitinates the target protein and subsequently leads to proteasome-dependent degradation. Defective proteasomal degradation has been linked to a variety of disorders, including Parkinson’s disease, muscular dystrophies, Alzheimer’s disease, cardiovascular disease, Huntington’s disease, and cancers. 
 
There are over 600 E3 ubiquitin ligases that facilitate ubiquitination of different proteins in vivo and are mainly divided into four families: U-box E3s, multisubunit E3s, HECT-domain E3s, and monomeric RING E3s. The first E3 ligase that successfully targeted a small molecule was MDM2, which ubiquitinates the tumor suppressor p53 protein. There are hundreds of E3 ligases in eukaryotes and hundreds more proteins involved in active E3 ligase complexes; however, very few have known binding compounds that could be used as recruiter molecules for PROTAC design. Currently only two proteins, von Hippel Lindau (VHL) and Cereblon (CRBN), substrate adaptor components of larger E3 Cullin-RING complexes, have shown significant and broad success against a diverse set of therapeutic targets. 
 
Cereblon is a thalidomide binding protein that forms part of an E3 ubiquitin ligase complex with Cullin 4 and the E2-binding protein ROC1, where it functions as a substrate receptor to select proteins for ubiquitination. Lenalidomide and pomalidomide are marketed class of immunomodulatory drugs (IMiDs), which are connected to their ability to promote the recruitment and ubiquitination of substrate proteins to the cullin-damaged DNA-binding-Ring box-domain protein (CUL4-DDBI-RBX1-CRBN), with the ubiquitin tagged proteins directed to and subsequently degraded by the 26S proteasome. Lenalidomide is further approved for treatment in 5q-deletion associated myelodysplastic syndrome patients, where clinical activity is associated with degradation protein kinase Ck1a substrate. GSPT1 (also named eRF3a) is a translation termination factor that binds eukaryotic translation termination factor 1 (eFR1) to mediate stop codon recognition and nascent protein release from the ribosome. Lenalidomide and pomalidomide do not promote the degradation of GSPT1, which demonstrates the selectivity in the zinc finger transcription factors such as Aiolos (IKZF3) and Ikaros (IKZF1). 
 
Ikaros and Aiolos are zinc finger transcription factors with critical roles in hematological development and differentiation and are associated with the downstream effects of degrading these proteins, which result in the mediation of antiproliferative and immunomodulatory activities of lenalidomide and pomalidomide. Ikaros and Aiolos are encoded by IKZF1 and IKZF3 genes, respectively, and were the first cereblon substrates identified, which demonstrated that the addition of cereblon modulating ligands triggers their recruitment and degradation. The polymorphisms of IKZF1 and IKZF3 are associated with a risk of developing systemic lupus erythematosus (SLE). 
 
In this Patent Highlight, the degronimers shown facilitated degradation of a targeted protein via the ubiquitin proteasome pathway (UPP), while the degrons bind to an E3 ubiquitin ligase (cereblon). Binding of the degron to cereblon results in increased interactions of cereblon to Aiolos or Ikaros, which subsequently leads to ubiquitination and degradation in the proteasome. As a result, the decreased levels of Aiolos or Ikaros leads to changes in transcriptional regulation of their downstream proteins. The degron can be used to treat disorder mediated by Aiolos or Ikaros, which include leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and multiple myeloma. Furthermore, the degronimer contain a “targeting ligand” that binds (noncovalently) to a selected target protein, a degron that binds to an E3 ligase (typically cereblon), and, optionally, a linker that covalently links the targeting ligand to the degron.