In the past years, it has emerged that numerous human tumors, such as neuroblastoma, can be caused by excessive activity, hyperproliferation, or deregulation of protein kinases and histone deacetylase enzymes. Protein kinases can transfer phosphate groups from triphosphate nucleotides to hydroxyl groups of serine, threonine, or tyrosine of specific proteins, while histone deacetylase enzymes (HDAC) play a key role in the removal of acetyl groups from the acetyl-L- lysine side chains of histone proteins, thereby contributing to chromatin remodeling. Normally, these enzymes are involved in various biological processes related to cell growth, but if deregulated, they may be the biomolecular cause of the tumor pathologies indicated above [1]. Aurora kinase proteins (AURK) play a crucial role in controlling chromosomal organization and regulating proper formation of the mitotic spindle during chromosome separation in daughter cells, and the AURK isoform A (AURKA) has long been recognized as a promising anti-tumor target [2]. HDAC enzymes, on the other hand, are involved in gene expression regulation and, under cancerous conditions, their deregulation can lead to alterations in the cell cycle, with abnormal tumor mass development. Various recent studies clearly demonstrate how an interaction between the two proteins is correlated with tumor mass development; indeed, in the context of neuroblastoma, HDAC enzymes can influence the transcription of genes encoding AURKA, so simultaneous inhibition of the two proteins can be advantageous in blocking tumor cell proliferation [3]. Therefore, considering the above, our research has focused on the design and synthesis of a series of molecules that could simultaneously exhibit inhibitory activity against both proteins. To date, no compounds has shown activity against both targets, so we started from AURKA inhibitors previously synthesized in our laboratory [4] and we modified the structure to incorporate a linker of different nature ending with a zinc binding group. Through docking studies and scaffold hopping, the zinc binding group used was chosen to mimic the one from the potent non-selective inhibitor Quisinostat. A small set of molecules has been synthetized and tested both in silico and vitro. The data coming from the biological assays will be shown and discussed.
Design and synthesis of novel compounds targeting both AURKA and HDAC enzymes / Ruggieri, G.; Madia, V. N.; Patacchini, E.; Ialongo, D.; Albano, A.; Messore, A.; Saccoliti, F; Arpacioglu, M.; De Leo, A.; Scipione, L.; Rotili, D.; Fiorentino, F.; Paiardini, A.; Di Santo, R.; Costi, R.. - (2024). (Intervento presentato al convegno EFMC-ISMC 2024 XXVIII EFMC International Symposium on Medicinal Chemistry tenutosi a Rome, Italy).
Design and synthesis of novel compounds targeting both AURKA and HDAC enzymes.
Madia V. N.;Patacchini E.;Ialongo D.;Albano A.;Messore A.;Arpacioglu M.;Scipione L.;Rotili D.;Fiorentino F.;Paiardini A.;Di Santo R.;Costi R.
2024
Abstract
In the past years, it has emerged that numerous human tumors, such as neuroblastoma, can be caused by excessive activity, hyperproliferation, or deregulation of protein kinases and histone deacetylase enzymes. Protein kinases can transfer phosphate groups from triphosphate nucleotides to hydroxyl groups of serine, threonine, or tyrosine of specific proteins, while histone deacetylase enzymes (HDAC) play a key role in the removal of acetyl groups from the acetyl-L- lysine side chains of histone proteins, thereby contributing to chromatin remodeling. Normally, these enzymes are involved in various biological processes related to cell growth, but if deregulated, they may be the biomolecular cause of the tumor pathologies indicated above [1]. Aurora kinase proteins (AURK) play a crucial role in controlling chromosomal organization and regulating proper formation of the mitotic spindle during chromosome separation in daughter cells, and the AURK isoform A (AURKA) has long been recognized as a promising anti-tumor target [2]. HDAC enzymes, on the other hand, are involved in gene expression regulation and, under cancerous conditions, their deregulation can lead to alterations in the cell cycle, with abnormal tumor mass development. Various recent studies clearly demonstrate how an interaction between the two proteins is correlated with tumor mass development; indeed, in the context of neuroblastoma, HDAC enzymes can influence the transcription of genes encoding AURKA, so simultaneous inhibition of the two proteins can be advantageous in blocking tumor cell proliferation [3]. Therefore, considering the above, our research has focused on the design and synthesis of a series of molecules that could simultaneously exhibit inhibitory activity against both proteins. To date, no compounds has shown activity against both targets, so we started from AURKA inhibitors previously synthesized in our laboratory [4] and we modified the structure to incorporate a linker of different nature ending with a zinc binding group. Through docking studies and scaffold hopping, the zinc binding group used was chosen to mimic the one from the potent non-selective inhibitor Quisinostat. A small set of molecules has been synthetized and tested both in silico and vitro. The data coming from the biological assays will be shown and discussed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
