Ricolinostat, also known as ACY-1215 or Rocilinostat, is an investigational drug being studied for its potential to treat certain blood disorders and cancers. It is an orally available compound, making it a convenient option for administration if it progresses through clinical development. This therapeutic agent has drawn scientific interest due to its unique biological activity.
Understanding Ricolinostat
Ricolinostat is a selective histone deacetylase 6 (HDAC6) inhibitor. Histone deacetylases (HDACs) are enzymes within cells that regulate gene expression by removing acetyl groups from histones, which are proteins that DNA wraps around, leading to a more compact DNA structure and reduced gene activity. Ricolinostat primarily targets HDAC6, a specific subtype. Unlike “pan-HDAC inhibitors” that affect multiple HDAC enzymes and can lead to broader side effects, ricolinostat’s selective inhibition aims for therapeutic benefits with a more favorable safety profile.
How Ricolinostat Works
Ricolinostat selectively inhibits HDAC6, an enzyme primarily located in the cytoplasm. This inhibition increases the acetylation of specific proteins, such as alpha-tubulin. Tubulin is a key component of microtubules, cellular structures involved in maintaining cell shape, transport, and division.
The inhibition of HDAC6 causes acetylated tubulin to accumulate, disrupting microtubule dynamics. This impacts protein trafficking and the degradation of misfolded proteins. In cancer cells, this can lead to an accumulation of unfolded proteins, inducing apoptosis and inhibiting cancer cell growth.
Primary Therapeutic Applications
Ricolinostat has been investigated for its use in treating various cancers, particularly hematological malignancies like multiple myeloma and lymphoma. In multiple myeloma, a blood cancer characterized by malignant plasma cell growth, ricolinostat has shown promising activity, especially when combined with other therapies. Studies have explored its use alongside proteasome inhibitors (e.g., bortezomib) and immunomodulatory drugs (e.g., lenalidomide or pomalidomide).
The rationale for its use in these cancers stems from HDAC6’s role in protein degradation pathways, which are often dysregulated in cancer cells. By inhibiting HDAC6, ricolinostat can enhance the effects of other anti-cancer drugs by disrupting the cell’s ability to manage misfolded proteins and inducing cell death. In multiple myeloma, ricolinostat’s selective inhibition of HDAC6 has shown potential to overcome resistance to proteasome inhibitors, a common challenge. Beyond cancers, ricolinostat has also been explored for conditions like painful diabetic peripheral neuropathy and Charcot-Marie-Tooth disease, where HDAC6 may play a role in nerve function. Preclinical studies have also investigated its potential to reverse chemotherapy-induced peripheral neuropathy.
Safety Profile and Side Effects
Clinical trials of ricolinostat, both alone and in combination, have established its safety profile. It has generally been well-tolerated. Common adverse events include fatigue, anemia, and diarrhea.
Reversible decreases in neutrophil counts (a type of white blood cell) have been noted, though significant reductions were uncommon. Diarrhea was more frequently observed at higher doses, specifically at or above 160 mg daily. Compared to non-selective HDAC inhibitors, ricolinostat has shown a more favorable safety profile, with less severe gastrointestinal and hematologic toxicities.
Ongoing Research and Development
Ricolinostat has progressed through various phases of clinical trials. These trials have evaluated its safety, preliminary effectiveness, and optimal dosing, often in combination with existing treatments for conditions like multiple myeloma. For example, trials have investigated ricolinostat with bortezomib and dexamethasone for relapsed or refractory multiple myeloma.
Current research explores new applications and combinations, with ongoing trials investigating its use with lenalidomide and dexamethasone, or with pomalidomide and dexamethasone. While some studies, such as those for painful diabetic peripheral neuropathy, have not shown a significant reduction in pain compared to placebo, the drug’s favorable safety profile supports its continued investigation in other neurological conditions and cancers.