Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Abstract

Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

“…Among these, the latest polypharmacology approach that is designed to overcome the limitations of single-target therapy appears to have a superior therapeutic effect along with reduced adverse reactions and diminished potential drug resistance. Specifically, the epigenetic polypharmacology approach which uses a dual-acting HDAC and PI3K inhibition by incorporating HDAC inhibitor functionality into a PI3K inhibitor pharmacophore is capable of potent anticancer activity by disrupting the oncogenic signaling network through simultaneous inhibition of HDACs and PI3K in cancer cells [15,16].…”

“…This letdown has encouraged new drug design and therapeutic approaches to provide lasting tumor suppression. The goal of drug discovery in the epi-drug research is no longer just the design of highly potent and selective drugs acting on a specific epi-target, but advancing towards designing network-active compounds with multitargeting capability through a polypharmacology approach [14][15][16][131][132][133][134].…”

“…Moreover, the latest polypharmacology approach that is designed to overcome the limitations of a single-target approach appears to have a superior therapeutic effect with an affiliated reduction in adverse reactions and diminished potential drug resistance. Specifically, the epigenetic polypharmacology approach, using a dual-acting HDAC and PI3K inhibitor, by incorporating HDACI functionality into a PI3KI pharmacophore, is capable of potent anticancer activity [14][15][16]. Simultaneous inhibition of HDACs and PI3K activity by the dual HDAC and PI3K inhibitor can disrupt the oncogenic signaling network in cancer cells [14][15][16].…”

“…Specifically, the epigenetic polypharmacology approach, using a dual-acting HDAC and PI3K inhibitor, by incorporating HDACI functionality into a PI3KI pharmacophore, is capable of potent anticancer activity [14][15][16]. Simultaneous inhibition of HDACs and PI3K activity by the dual HDAC and PI3K inhibitor can disrupt the oncogenic signaling network in cancer cells [14][15][16]. This review will focus on the role of HDACs and PI3K signaling in malignancy.…”

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

“…9,27,28,112,166,169,[205][206][207][208][209][210][211] However, because Klotho does not cross the bloodbrain barrier, 10,212 a small molecule approach aimed at inducing endogenous Klotho activity and expression in the CNS is surfacing as a promising therapeutic strategy. 27,81,90,143,213,214 Epigenetics 10,90,100,169,[215][216][217][218][219] and gene therapy-based methods are part of the emerging landscape under investigation. 19,215,220,221 Amyotrophic Lateral Sclerosis The global prevalence of ALS is estimated to be roughly two to four cases per 100,000 population 222,223 compared with *30 cases per 100,000 population for MS. 168 ALS (also referred to as progressive muscular atrophy or Lou Gehrig's disease) is a devastating neurodegenerative disease.…”