Daiqing Liao

Demonstrates In Vivo Safety and Efficacy in Breast Cancer Models

This set of anticancer compounds selectively degrades or inhibits cancer-related histone deacetylase proteins. These proteins are commonly overexpressed in various cancer types, and class I histone deacetylase proteins activate oncogenes that cause tumor formation, cancer progression, and treatment resistance. In addition to their role in cancers, when dysregulated, these proteins can cause the onset of inflammatory and metabolic disorders. Histone deacetylase inhibitors are promising anticancer therapies but have previously been prone to undesirable off-target activity.

 

Researchers at the University of Florida have identified first-in-class benzoylhydrazide-containing compounds that inhibit or destroy specific proteins by acting as a molecular glue that targets class I histone deacetylase complexes. One of these compounds has shown in vivo safety and potent anticancer activities in breast cancer models.

 

 

Application

Treatment of cancer and other human diseases by targeting class I histone deacetylase-containing complexes for proteasome degradation

 

Advantages

• Benzoylhydrazide-based compounds selectively inhibit or destroy class I histone deacetylase complexes, limiting undesirable off-target activity
• Includes compounds that cause protein degradation, increasing potency of therapy compared to protein inhibition alone
• Targets class I histone deacetylase proteins related to cancer, inflammatory, and metabolic disorders, making the potential therapeutic applications diverse
• Uses novel mechanism of action, improving treatment efficacy

Technology

Benzoylhydrazide compounds that selectively inhibit or degrade cancer-related proteins by targeting class I histone deacetylase complexes. These compounds specifically target histone deacetylase-associated lysine-specific demthylase1 (LSD1) and the scaffolding protein (CoREST1) for proteasomal degradation. One compound, SR-4370, shows excellent in vivo safety and potent anticancer efficacy in multiple in vivo cancer models.

Compounds Display Potent Inhibition of Cancer-Causing Enzymes and Suppression of Solid Tumor Growth

This class of small-molecule HDAC inhibitors has a novel benzoylhydrazide scaffold with potential to treat cancer, neurodegenerative disorders, and metabolic diseases. Cancer is the second leading cause of death in the United States, with more than 1.5 million people diagnosed every year. There are four HDAC inhibitors approved for cancer therapy, but those are only approved for treating hematologic malignancies such as T-cell lymphomas and multiple myelomas. Additionally, HDAC inhibitors undergoing clinical trials are continuing to face issues with dose-limiting toxicity and efficacy against solid tumors and other human diseases. Therefore, the market is in need of an HDAC inhibitor with broad therapeutic applications and low toxicity that can meet the stringent criteria for FDA approval. Researchers at the University of Florida in collaboration with scientists at the Scripps Research Institute have conducted a high-throughput screening and identified a group of benzoylhydrazide HDAC inhibitors that induces histone hyperacetylation and suppresses cancer cell proliferation. Medicinal chemistry efforts have led to optimized analogs with low nanomolar HDAC inhibition potency. Initial in vivo animal experiments show that these compounds are not toxic and exhibit good pharmacokinetic properties. These compounds are under active preclinical development for cancer therapy.

Application

HDAC inhibitor for treating cancer and other diseases (neurologic, cardiovascular, and metabolic disorders)

Advantages

• Demonstrates potential for broad therapeutic applications, offering treatment for various forms of cancer and other diseases
• Exhibits class I HDAC isoform-specificity and low toxicity, outperforming current HDAC inhibitors in clinical trials

Technology

University of Florida researchers have discovered a group of benzoylhydrazide compounds through a high-throughput screen and medicinal chemistry efforts that could potentially treat cancer, neurodegenerative disorders, and metabolic diseases. The compounds display potent in vitro inhibition of class I HDACs and inhibited cancer growth in vitro. The compounds? inhibitory activity was confirmed in cell-based assays and suppressed cancer cell proliferation of diverse cancer cell lines. In vivo animal experiments indicate that these compounds are safe and exhibit good pharmaceutical properties. The benzoylhydrazide HDAC inhibitor is currently under active preclinical development for cancer therapy.

Inhibits Lipogenesis in Specific Cells to Prevent Cancerous Tumor Growth

This cancer treatment obstructs the lipogenesis metabolic pathways in cancerous cells, directly inhibiting tumor growth with minimal side effects. A variety of cancerous cells, including those responsible for breast, prostate, and colon cancers, depend on increased lipogenesis to supply lipids for rapid cell proliferation and tumor growth. Compounds that inhibit this function, therefore, could have broad therapeutic application. Cancer is the second leading cause of death the United States, according to the CDC. As the number of people suffering from cancer increases, analysts project the global cancer therapeutics market to grow to $182 billion by 2023 . The conventional cancer treatment is chemotherapy, but this also damages healthy cells and causes many side effects. Targeted therapy allows for customized treatment and less harm to healthy cells, but further research is necessary to understand the broader effects of targeting intracellular metabolic pathways.

 

Researchers at the University of Florida have discovered a cancer therapeutic that inhibits tumor growth by targeting the cell lipogenesis pathway. Cancer cells need lipids for proliferation and communication with neighboring cells. This peptide drug impairs lipid synthesis and shows anti-cancer activity against a variety of cancer types in vitro and in vivo using mouse cancer models.

 

 

Application

Peptide drug that inhibits cancer growth for the treatment of various types of cancer

 

Advantages

• Targets and decreases lipid production, reducing cancer cell proliferation
• Naturally permeates cancer cell membranes, aiding cellular uptake for more efficient delivery
• Low off-target toxicity, minimizing potential side effects
• Targets a pathway intrinsic to a wide variety of cancer types, showing potential for broad therapeutic application

Technology

This first-of-its-kind peptide inhibits de novo lipogenesis in cells to prevent tumor growth in vivo. Lipogenesis is a major metabolic pathway that is elevated in cancer cells and helps drive tumor growth. The short peptide impairs expression of key lipogenic regulators to attenuate the growth of tumors. Experimental results indicate an anti-cancer effect in vivo, establishing a class of therapeutics against various cancers including breast, colon, and prostate cancers.