CC-885: Cutting-Edge Cereblon Modulator and Its Role in Mitophagy

Targeted protein degradation has emerged as a promising strategy for drug development, with cereblon modulators playing a key role. CC-885, a potent cereblon modulator, has drawn attention for its ability to influence cellular pathways beyond traditional protein degradation targets.

Studies suggest CC-885 impacts mitophagy, the selective degradation of mitochondria, adding another layer to its biological effects. Understanding how CC-885 interacts with intracellular processes provides insight into its therapeutic potential.

Role Of Cereblon In Protein Degradation

Cereblon (CRBN) functions as a substrate receptor within the Cullin-RING E3 ubiquitin ligase complex (CRL4^CRBN), directing proteins toward ubiquitination and degradation by the proteasome. This process regulates protein turnover and prevents the accumulation of misfolded or dysfunctional proteins. CRBN’s significance in targeted protein degradation became evident with the discovery that small molecules, including immunomodulatory drugs (IMiDs) like thalidomide, lenalidomide, and pomalidomide, can modulate its substrate specificity. These compounds induce the recruitment of neosubstrates, leading to their ubiquitination and degradation, a mechanism exploited in treating hematologic malignancies.

CRBN’s role as a molecular adaptor for protein degradation is dictated by its interaction with small-molecule ligands, which alter its substrate-binding preferences. Structural studies show these ligands induce conformational changes in CRBN, enabling it to recognize and ubiquitinate proteins that would otherwise escape degradation. For instance, lenalidomide and pomalidomide promote the degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors essential for multiple myeloma cell survival. This mechanism has revolutionized drug development, leading to novel cereblon modulators with enhanced specificity and potency.

Beyond endogenous substrate degradation, CRBN has been leveraged in proteolysis-targeting chimeras (PROTACs), bifunctional molecules that link a target protein to an E3 ligase for selective degradation. By recruiting neosubstrates, PROTACs expand the range of druggable proteins, offering a strategy to eliminate disease-associated proteins that lack traditional binding pockets for small-molecule inhibitors. This approach has gained traction in oncology and neurodegenerative diseases, where aberrant protein accumulation drives pathology.

Key Structural Insights On CC-885

CC-885 stands out among cereblon modulators due to its distinct structural features that enhance binding affinity and substrate specificity. Unlike earlier IMiDs, CC-885 incorporates a unique phthalimide scaffold with additional substituents that optimize its interaction with cereblon’s thalidomide-binding domain. This structural refinement strengthens the molecular interface between CC-885 and cereblon, leading to more efficient recruitment of neosubstrates. Crystallographic studies reveal CC-885 establishes a deeper binding pocket within cereblon compared to traditional IMiDs, facilitating the degradation of a broader range of target proteins.

A defining characteristic of CC-885 is its ability to induce the degradation of GSPT1, a translation termination factor not typically targeted by other cereblon modulators. Structural analysis indicates CC-885 stabilizes a ternary complex between cereblon and GSPT1, positioning the latter for ubiquitination and degradation. This specificity is attributed to the extended molecular contacts CC-885 forms within the cereblon-binding domain, enhancing its selectivity for neosubstrates beyond the IKZF family. The degradation of GSPT1 has been linked to potent anti-proliferative effects in cancer models.

The enhanced binding affinity of CC-885 is supported by thermodynamic and kinetic studies, which demonstrate a lower dissociation rate compared to lenalidomide and pomalidomide. This prolonged interaction time suggests CC-885 maintains a more stable engagement with cereblon, allowing for sustained ubiquitination activity. Additionally, structural modifications in CC-885 contribute to an altered hydrogen bonding network within the cereblon complex, reinforcing its binding stability. These changes improve potency while reducing off-target interactions, a factor instrumental in its preclinical development.

Mechanism Of Action In The Ubiquitin-Proteasome Pathway

CC-885 modulates the ubiquitin-proteasome system, a pathway responsible for protein degradation in eukaryotic cells. As a cereblon modulator, CC-885 enhances the recruitment of specific neosubstrates to the CRL4^CRBN E3 ubiquitin ligase complex, facilitating their ubiquitination and degradation. This process begins with CC-885 binding to cereblon’s thalidomide-binding domain, inducing a conformational shift that alters the substrate recognition profile of the ligase complex. Unlike traditional cereblon modulators, CC-885 exhibits broader substrate specificity, enabling it to target proteins previously unaffected by IMiDs like lenalidomide or pomalidomide.

A key feature of CC-885’s mechanism is its ability to promote the degradation of GSPT1, a translation termination factor implicated in cellular proliferation. Structural studies reveal CC-885 stabilizes an interaction between cereblon and GSPT1, positioning the latter for polyubiquitination and degradation. The depletion of GSPT1 disrupts ribosomal function, leading to impaired protein synthesis and selective cytotoxicity in malignant cells. This mechanism has been particularly evident in hematologic cancers, where GSPT1 degradation induces apoptosis and suppresses tumor growth.

The efficiency of CC-885 in driving ubiquitination is influenced by its binding kinetics and molecular stability within the cereblon complex. Studies using surface plasmon resonance demonstrate CC-885 exhibits a prolonged residence time on cereblon, allowing for sustained substrate recruitment and degradation. This prolonged interaction enhances potency relative to earlier cereblon modulators by ensuring continuous depletion of target proteins. Additionally, proteomic analyses indicate CC-885 influences the degradation of multiple neosubstrates beyond GSPT1, expanding its functional impact within the ubiquitin-proteasome system.

Mitophagy Inhibition Observations

Investigations into CC-885’s cellular effects have highlighted its unexpected influence on mitophagy, the selective degradation of damaged mitochondria via autophagic pathways. While mitophagy is essential for mitochondrial quality control and oxidative stress prevention, CC-885 appears to interfere with this process. In cellular models, treatment with CC-885 resulted in an accumulation of dysfunctional mitochondria, suggesting a blockade in mitophagic flux. This effect was particularly evident in studies using mitochondrial stressors such as carbonyl cyanide m-chlorophenyl hydrazone (CCCP), where cells exposed to CC-885 failed to clear depolarized mitochondria efficiently.

One proposed mechanism involves CC-885’s interaction with mitophagy regulators, including PINK1 and Parkin, which coordinate tagging of damaged mitochondria for autophagic degradation. Under normal conditions, PINK1 stabilizes on the outer mitochondrial membrane of dysfunctional organelles, recruiting Parkin to ubiquitinate mitochondrial proteins and signal their removal. However, CC-885-treated cells exhibited reduced Parkin recruitment, impairing the ubiquitination of mitochondrial substrates and preventing their recognition by the autophagic machinery. This disruption in ubiquitin signaling may stem from CC-885’s modulation of E3 ubiquitin ligase activity, indirectly affecting pathways required for mitochondrial turnover.

Interplay With Intracellular Signaling

CC-885’s impact extends beyond targeted protein degradation, influencing intracellular signaling networks that regulate cell survival, stress responses, and metabolism. By modulating cereblon-dependent ubiquitination, CC-885 alters the stability of proteins involved in signal transduction, leading to downstream effects on cellular physiology. One notable consequence of CC-885 treatment is the disruption of protein homeostasis in rapidly dividing cells, particularly in cancer models where dysregulated signaling drives uncontrolled proliferation. The degradation of GSPT1, for example, not only affects translation termination but also interferes with pathways linked to cell cycle progression, reinforcing the compound’s cytotoxic effects.

Beyond its effects on cell growth, CC-885 has been shown to modulate pathways associated with mitochondrial function and energy metabolism. Given its inhibition of mitophagy, disruptions in mitochondrial quality control may lead to altered reactive oxygen species (ROS) production and changes in redox signaling. Elevated ROS levels can activate stress-responsive kinases such as p38 MAPK and JNK, which influence apoptotic and survival pathways depending on cellular context. In certain cancer cell lines, CC-885 treatment has been associated with increased oxidative stress and enhanced sensitivity to mitochondrial dysfunction, suggesting a potential therapeutic window for exploiting its effects in malignancies dependent on mitochondrial integrity. The compound’s ability to reshape intracellular signaling networks highlights its broader biological impact, warranting further investigation into its applications beyond targeted protein degradation.