In recent years, it has become apparent that numerous human tumors, including neuroblastoma, can result from excessive activity, hyperproliferation, or dysregulation of protein kinases and histone deacetylase enzymes. Protein kinases facilitate the transfer of phosphate groups from triphosphate nucleotides to hydroxyl groups of serine, threonine, or tyrosine on specific proteins, while histone deacetylase enzymes (HDAC) are pivotal in removing acetyl groups from the acetyl-L-lysine side chains of histone proteins, thus contributing to chromatin remodeling. Typically, these enzymes are involved in various biological processes related to cell growth. However, when deregulated, they can serve as biomolecular triggers for the tumor pathologies mentioned [1]. Aurora kinase proteins (AURK) are essential in governing chromosomal organization and ensuring proper formation of the mitotic spindle during chromosome separation in daughter cells. Among them, the AURK isoform A (AURKA) has long been recognized as a promising anti-tumor target [2]. Conversely, HDAC enzymes participate in gene expression regulation, and their dysregulation under cancerous conditions can disrupt the cell cycle, contributing to abnormal tumor growth. Recent studies have elucidated the correlation between the interaction of these two proteins and tumor progression. Specifically, in the context of neuroblastoma, HDAC enzymes can impact the transcription of genes encoding AURKA, suggesting that simultaneous inhibition of both proteins could be advantageous in impeding tumor cell proliferation [3]. In light of these findings, our research has centered on designing and synthesizing a series of molecules capable of simultaneously inhibiting both proteins. To date, no compounds have demonstrated activity against both targets. Therefore, we began with AURKA inhibitors previously synthesized in our laboratory [4], modifying their structure to incorporate a linker of different nature culminating in a zinc binding group. Through docking studies and scaffold hopping, we selected a zinc binding group that mimics the one found in the potent non-selective inhibitor Quisinostat. A small set of molecules has been synthesized and subjected to both in silico and in vitro testing. The biological assay data will be presented and analyzed.
DEVELOPING NOVEL COMPOUNDS TARGETING AURKA AND HDAC ENZYMES SIMULTANEOUSLY / Arpacioglu, M.; Madia, V. N.; Patacchini, E.; Ialongo, D.; Albano, A.; Messore, A.; Ruggieri, G.; De Leo, A.; Scipione, L.; Rotili, D.; Fiorentino, F.; Paiardini, A.; Di Santo, R.; Costi, R.. - (2024). (Intervento presentato al convegno The European Federation for Medicinal Chemistry Young Medicinal Chemists' Symposium tenutosi a Roma, Italia).
DEVELOPING NOVEL COMPOUNDS TARGETING AURKA AND HDAC ENZYMES SIMULTANEOUSLY
Arpacioglu, M.Primo
;Madia, V. N.;Patacchini, E.;Ialongo, D.;Albano, A.;Messore, A.;Scipione, L.;Fiorentino F.;Di Santo, R.;Costi, R.
2024
Abstract
In recent years, it has become apparent that numerous human tumors, including neuroblastoma, can result from excessive activity, hyperproliferation, or dysregulation of protein kinases and histone deacetylase enzymes. Protein kinases facilitate the transfer of phosphate groups from triphosphate nucleotides to hydroxyl groups of serine, threonine, or tyrosine on specific proteins, while histone deacetylase enzymes (HDAC) are pivotal in removing acetyl groups from the acetyl-L-lysine side chains of histone proteins, thus contributing to chromatin remodeling. Typically, these enzymes are involved in various biological processes related to cell growth. However, when deregulated, they can serve as biomolecular triggers for the tumor pathologies mentioned [1]. Aurora kinase proteins (AURK) are essential in governing chromosomal organization and ensuring proper formation of the mitotic spindle during chromosome separation in daughter cells. Among them, the AURK isoform A (AURKA) has long been recognized as a promising anti-tumor target [2]. Conversely, HDAC enzymes participate in gene expression regulation, and their dysregulation under cancerous conditions can disrupt the cell cycle, contributing to abnormal tumor growth. Recent studies have elucidated the correlation between the interaction of these two proteins and tumor progression. Specifically, in the context of neuroblastoma, HDAC enzymes can impact the transcription of genes encoding AURKA, suggesting that simultaneous inhibition of both proteins could be advantageous in impeding tumor cell proliferation [3]. In light of these findings, our research has centered on designing and synthesizing a series of molecules capable of simultaneously inhibiting both proteins. To date, no compounds have demonstrated activity against both targets. Therefore, we began with AURKA inhibitors previously synthesized in our laboratory [4], modifying their structure to incorporate a linker of different nature culminating in a zinc binding group. Through docking studies and scaffold hopping, we selected a zinc binding group that mimics the one found in the potent non-selective inhibitor Quisinostat. A small set of molecules has been synthesized and subjected to both in silico and in vitro testing. The biological assay data will be presented and analyzed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
