Medicinal chemistry of histone deacetylase inhibitors

Abstract

Today, we are witnessing an explosion of scientific concepts in cancer chemotherapy. It has been considered for a long time that genetic instability in cancer should be treated with drugs that directly damage the DNA. Understanding the molecular basis of malignant diseases shed light on studying phenotypic plasticity. In the era of epigenetics, many efforts are being made to alter the aberrant homeostasis in cancer without modifying the DNA sequence. One such strategy is modulation of the lysine acetylome in human cancers. To remove the acetyl group from the histones, cells use the enzymes that are called histone deacetylases (HDACs). The disturbed equilibrium between acetylation and deacetylation on lysine residues of histones can be manipulated with histone deacetylase inhibitors (HDACi). Throughout the review, an effort will be made to present the mechanistic basis of targeting the HDAC isoforms, discovered selective HDAC inhibitors, and their therapeutical implications and expectations in modern drug discovery.

Savremena hemoterapija kancera se bazira na velikom broju različitih naučnih pristupa. Dugo se smatralo da bi genetsku nestabilnost u kancerskim oboljenjima trebalo lečiti agensima koji direktno oštećuju DNK. Razumevanje molekularnih osnova malignih oboljenja rasvetlilo je značaj fenotipske plastičnosti. U eri epigenetike, učinjeni su mnogi napori da se izmeni aberantna homeostaza u kancerskom oboljenju bez modifikovanja sekvence DNK. Jedna od takvih strategija je modulacija lizinskog acetiloma u humanim kancerima. Da bi se acetil grupa uklonila sa histona, ćelije koriste enzime histon deacetilaze. Poremećena ravnoteža acetilacije i deacetilacije na lizinskim ostacima histona može biti regulisana inhibitorima histon deacetilaza. Kroz ovaj pregledni rad, biće prikazani mehanizmi inhibicije izoformi histon deacetilaza, različiti inhibitori histon deacetilaza, kao i njihove terapijske primene i očekivanja u modernom razvoju lekova.