Researchers Develop Improved Anti-tumor Agent
#BreakDownCancer
Researchers Develop Improved Anti-tumor Agent
#BreakDownCancer
Research Terms
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.
Treatment of cancer and other human diseases by targeting class I histone deacetylase-containing complexes for proteasome degradation
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.
This naturally occurring compound with anti-cancer properties has the potential to revolutionize cancer treatment by providing tailored therapies with reduced side effects. Cancer remains a significant health issue in the United States, with considerable unmet medical needs. Available cancer treatments such as chemotherapy and radiation therapy are limited by factors including toxicity and drug resistance. Hence, it is necessary to develop more accurate and effective cancer treatments that produce fewer side effects. An emerging form of cancer therapy involves using proteolysis-targeting chimeras (PROTACs). PROTACs are bifunctional molecules consisting of two covalently linked components – a ligand that targets a protein of interest and a ligand that recruits an E3 ligase, which facilitates the degradation of the target protein. By hijacking the natural cellular protein degradation process, PROTACs can eliminate undesirable cancer-associated proteins, such as kinases, with greater precision than traditional therapies. The use of PROTACs is limited by the absence of diverse ligands for E3 ligases, an essential component of PROTACs.
Researchers at the University of Florida have identified Piperlongumine, a naturally occurring compound with anti-cancer properties, as a possible ligand for E3 ligases. PROTACs have been synthesized by conjugating Piperlongumine to a CDK9 inhibitor (SNS-032) currently used as a cancer therapeutic. A lead conjugate, 955, has been discovered to potently degrade CDK9 and CDK10 in a ubiquitin-proteasome dependent manner. This advancement in PROTAC technology has the potential to revolutionize cancer treatment by addressing the scarcity of ligands for E3 ligases, leading to tailored cancer therapies with reduced side effects.
Biological conjugate of E3 ligase ligand and CDK9 inhibitor that targets and degrades cancer-associated proteins of interest
PROTACs, an emerging form of cancer therapy, hijack the cellular ubiquitin-proteasome system (UPS) and degrade cancer-related proteins of interest. They are bifunctional molecules consisting of two pharmacophores. The first pharmacophore is a ligand that targets a cancer-associated protein of interest, while the second pharmacophore recruits an E3 ligase that facilitates the polyubiquitination and subsequent proteasome degradation of the target protein. Piperlongumine, a naturally occurring compound with anti-cancer and anti-aging properties, has been discovered to serve as the second pharmacophore due to its binding ability to bind several E3 ligases. CDK9 inhibitors such as SNS-032 are used as cancer therapeutics and can serve as the second pharmacophore in a PROTAC. UF researchers covalently conjugated Piperlongumine to SNS-032 and identified the most potent conformation, PROTAC conjugate 955. Conjugate 955 is a potent anticancer therapeutic as it recruits Kelch-like ECH-associated protein 1 (KEAP1) E3 ligase which mediates the proteasomal degradation of CDK9 and CDK10. These results show that Piperlongumine is a distinct E3 ligase ligand that can be used to synthesize effective anticancer PROTACs.
These polymerase theta inhibitors treat Epstein-Barr virus (EBV)-associated cancers and related diseases. EBV cancers are linked to two percent of the global cancer burden and are difficult to treat, demonstrating a strong need for effective treatment alternatives1. Cancer cell reproduction is heavily dependent on control over molecular mechanisms to repair DNA damage. While these cells usually use a variety of mechanisms to achieve this goal, if a mechanism is damaged, the cancer cells become even more dependent on alternative DNA repair mechanisms. These drug candidates treat EBV cancers by targeting the disease’s new dependence. Each year, EBV causes 200,000-300,000 new cases worldwide, and available therapeutics pose significant challenges. Such treatments are often associated with poor response, relapse, organ rejection, or long-term B-cell immunodeficiency, depending on the treatment method used.
Researchers at the University of Florida developed several PROTACs to effectively degrade polymerase theta. This treatment platform offers advantages compared to current options, providing a safer and potentially more effective approach. Because EBV-driven cancer cells lack a primary DNA repair pathway, they become reliant on compensatory repair mechanisms, specifically TMEJ (Theta-Mediated End Joining), and are more susceptible to PARP inhibition, prompting researchers to develop this therapeutic platform to target EBV-associated malignancies.
Polymerase-theta inhibitors are used to block TMEJ, which, when used alone or in combination with other therapies (such as R-CHOP, PARP inhibitors, etc), effectively target EBV-cancer cells
When cancer cells lose one type of DNA repair mechanism, they become overly dependent on alternative types of repair mechanisms. As a result, these cells become more responsive to treatments targeting these other mechanisms. EBV cancer cells rely on theta-mediated end joining (TMEJ) when they lose the function of the repair mechanism, homologous recombination. There is now an effort to inhibit TMEJ through polymerase theta. A key characteristic of TMEJ is the upregulation of polymerase-theta. When this polymerase is degraded, TMEJ fails. The platform is to be used with PARP inhibitors (which inhibit conventional DNA repair mechanisms) and/or agents that increase DNA damage to treat EBV-cancers. Dr. Bhaduri’s lab within the UF College of Medicine, in collaboration with Dr. Zheng’s lab within the UF College of Pharmacy, has developed several candidates that are effective at degrading polymerase theta. These candidates can be used to assist in treating EBV cancers.
This dual targeting agent reactivates the Epstein-Barr virus (EBV) to treat cancer patients by targeting enzymes that support the EBV latent state and thereby, uncontrolled EBV-cancer cell growth. The Epstein-Barr virus is a human herpesvirus infecting most humans. It is one of the two members of the gamma-herpesvirus family known to cause cancer in humans, infecting B cells of the immune system and epithelial cells. Once EBV’s initial lytic infection is brought under control, EBV latency persists in the individual’s B cells for the rest of their life. Most people become infected with EBV and gain adaptive immunity. In the United States, about half of all five-year-old children and about 90% of adults have evidence of previous infection.
EBV is associated with various non-malignant, premalignant, and malignant lymphoproliferative diseases, such as Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, post-transplant lymphoproliferative disease/lymphoma, nasopharyngeal cell carcinoma, and gastric carcinoma. Lymphomas are among the most common blood cancers in the United States, with over 80,000 new cases of Hodgkin’s and Non-Hodgkin’s lymphoma diagnosed annually. Oncolytic therapies destroy cancer cells by purposefully reactivating the lytic phase of EBV resulting in cancer cell death directly and indirectly through the genomic incorporation of an antiviral. Molecules that induce the lytic phase of EBV include DNA methyltransferase inhibitor, immunoglobulins, and HDAC inhibitors. Current therapies rely heavily on pan-HDAC inhibitors, which non-selectively block many enzymes, leading to significant toxicity, resistance, and limited long-term efficacy.
Researchers at the University of Florida have developed a dual targeting agent to selectively degrade HDAC3 and HDAC8-- enzymes directly linked to the viral latent state and therefore lymphoma progression. By guiding these enzymes to the cell’s natural recycling system for complete removal, the targeting agent delivers deeper, selective, and longer-lasting therapeutic effects with the potential for fewer side effects and improved patient outcomes.
Targets enzymes, HDAC3 and HDAC8, to reactivate the Epstein-Barr virus in cancer cells for targeted and improved treatment
This oncolytic dual-targeting agent is a next-generation protein degrader targeting HDAC3 and HDAC8. These enzymes help control and determine the genes expressed and active in cancer. Instead of simply blocking enzyme activity for a short time, the targeting agent guides HDAC3 and HDAC8 to the cell’s natural recycling system and tags them for removal. Rather than blocking the enzyme, it deletes it completely. By clearing the proteins from the cell, it delivers deeper and longer-lasting control with the potential for fewer off-target effects and less resistance.
