Novel Approaches for Developing Small Molecules to Target Histone Deacetylases
Cao, Fangyuan
DOI:
10.33612/diss.157448844
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Cao, F. (2021). Novel Approaches for Developing Small Molecules to Target Histone Deacetylases. University of Groningen. https://doi.org/10.33612/diss.157448844
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1
CHAPTER
1. Epigenetics and histone lysine acetylation
During the last decades, epigenetics has been defined as a crucial factor in cancer and inflammatory diseases. Epigenetics encompasses all inheritable changes in gene expression of eukaryotic cells without changes in the genetic code [1]. It is an inheritable and reversible process that is regulated by a range of enzymes. These enzymes dynamically modify the chromatin by adding or removing the so-called epigenetic modifications such as methylation, acetylation, phosphorylation, sumoylation, ubiquitination, ADP-ribosylation, N-acetylglucosylation and others [2]. Altogether these modifications form the so-called histone code, which plays a key role in the regulation of gene transcription.
After the discovery of epigenetic modifications in 1964 [3], histone acetylation has become a widely studied process that has been linked to various diseases including many types of cancer and inflammatory diseases. Generally, histone acetylation is loosening the chromatin structure, which facilitates gene transcription. The overall levels of histone acetylation are controlled by a balance between two groups of enzymes, histone acetylases (HATs) and histone deacetylases (HDACs). HATs transfer acetyl groups from Acetyl-CoA onto histone lysine residues, which neutralizes their positive charged and consequently their association with negatively charged DNA [4]. HDACs catalyze hydrolysis of acetylated lysine residues, which consequently provides a more condensed chromatin structure that is less accessible for the transcription machinery [5]. Thus, the activity balance of HATs and HDACs plays a key role in regulation of gene transcription.
Besides their activity on histones, both HATs and HDACs play an important role in acetylation and deacetylation of non-histone proteins, for example, α-tubulin and transcription factor kappa-light-chain-enhancer of activated B cells (NF-κB) [6,7]. HDAC6 deacetylases α-tubulin and heat shock protein 90 (HSP90) to regulate cell proliferation, metastasis, invasion, and mitosis in tumors [8]. HATs, such as the p300/CBP complex, are important chromatin modulators that directly interact with NF-κB [9,10]. HDAC 1, 2 and 3 are also reported to be involved in the regulation of the NF-κB signaling pathway [11,12]. NF-κB signaling pathway plays a critical role in regulating the survival, activation and differentiation of innate immune cells [13]. Therefore, unraveling the relationships between HATs/HDACs and NF-κB would pave the way for understanding the role of HATs and HDACs in inflammatory diseases.
2. Histone deacetylases (HDACs)
To date, eighteen HDAC subtypes are known, which are divided into two families and four classes, based on sequence similarity and cofactor dependency [14]. The first family consists of HDAC classes I, II, and IV, and comprises the “classical” zinc-dependent HDACs, while class III consists of the NAD+-dependent sirtuin (SIRT1-7) family. Generally, class I HDACs, which are HDAC 1, 2, 3, and 8, are located primarily in the nucleus. Class II HDACs, which comprises class IIA, including HDAC 4, 5, 7, and 9, and class IIB, including HDAC6 and HDAC 10, also have major cytoplasmic functions. HDAC 11 is the only class IV HDAC, which together with HDAC 10, is still poorly understood HDAC subtype. The class III sirtuins contain both mono-ADP-ribosyltransferase and histone deacetylase activity, and are located in the nucleus, the mitochondria, or the cytoplasm, depending on the isoform.
3. HDACs in cancer and inflammation
It is well known that HDACs play crucial roles in cancer by deacetylating histone and nonhistone proteins, which are involved in the regulation of cell cycle progression [15], apoptosis [16], DNA-damage response pathways [17], autophagy [18], and other cellular processes [19]. Four HDAC inhibitors, Vorinostat, Belinostat, Panobinostat and Romidepsin, have been approved by U.S. Food and Drug Administration (FDA) for clinical use for the treatment of lymphoma [20]. Currently, more HDAC inhibitors are being developed in clinical trials to treat various types of cancer, including multiple myeloma, lung cancer, breast cancer and non-small cell lung cancer (NSCLC) (Table1). The first HDAC inhibitor on the market was Vorinostat (also denoted SAHA), which contains a hydroxamic acid as zinc binding group. Subsequently, other hydroxamic acid-based HDAC inhibitors, Belinostat and Panobinostat, gained market approval. Currently, the next generation of hydroxamic acid-based HDAC inhibitors, including Resminostat, Givinostat, Pracinostat, Ricolinostat, Abexinostat and AR-42 are under clinical investigation. Another class of HDAC inhibitors are the o-aminoanilide-based inhibitors, such as Entinostat, selectively targeting class I HDACs. Entinostat and its analogs, Mocetinostat, Tacedinaline, Chidamide are in different phases of clinical investigation. Another type of HDAC inhibitors is Romidepsin, which is a natural product isolated from the
bacterium Chromobacterium violaceum. This inhibitor gained FDA approval for treatment of
HDAC activity and are now in phase I clinic trials. These achievements in the development of HDAC inhibitors encourage further studies to define the roles of HDAC isoenzymes and their potential utility as drug targets in different disease models. Furthermore, these achievements indicate the importance to develop novel types of HDAC inhibitors with improved selectivity profiles, enhanced physical-chemical properties and less toxicity to expand their scope of application.
A promising application for HDAC inhibitors is combination therapy with immune check point modulators to improve cancer immunotherapy [21,22]. On one hand, HDAC inhibition transcriptionally regulated PD-1 or PD-L1 expression in cells [22,23], which facilitates the susceptibility for immunotherapy. On the other hand, HDAC inhibitors alter the tumor microenvironment (TME) by influencing secretion of cytokines from immune cells [24]. This would also improve immunotherapy. For now, some of the widely used HDAC inhibitors, such as SAHA and Entinostat, have been used in clinical trials in combination with various immunomodulators [25]. Therefore, novel combination therapies, such as immune-epigenetic combination therapies, are being explored to leverage the efficacy of immunotherapy. Combination therapy of HDAC inhibitors and other anti-cancer agents has become a promising approach to overcome resistance to cancer therapy. Inhibition of HDAC 3 or HDAC 8 sensitized TRAIL-induced apoptosis in colon cancer cells [26]. Treatment of HDAC inhibitor could regain chemosensitivity in cisplatin-resistant cancer cells [27,28]. Studies have demonstrated that epidermal growth factor receptor (EGFR) inhibitor, Gefitinib, combined with Entinostat synergistically induces growth inhibition and apoptosis in Gefitinib-resistant NSCLC cells [29]. Using HDAC inhibitors as chemosensitizers that increase the efficiency of other chemotherapeutic compounds has shown great potential in preclinical and clinical trials.
Table 1. HDAC inhibitors under clinical investigations.
Substantial evidence has documented roles for HDACs in innate immune pathways [47]. HDACs regulate mature macrophage and dendritic cell (DC) function by controlling expression of inflammatory cytokines [48]. It has been proven that HDAC inhibitors are effective in animal models of several inflammatory diseases, such as chronic obstructive pulmonary disease (COPD) [49], asthma [50] and arthritis [40]. Of particular interest, HDAC inhibitors are observed to be effective at 10-100 fold lower doses in the treatment of inflammation than those used for treatment of cancer [52]. Inhibition of HDACs can suppress inflammatory activation of synovial macrophages from patients with rheumatoid arthritis [53]. Inhibition of HDAC 1, 2 and 3 by Entinostat in a COPD mouse model led to increased activity of NF-κB, increased translocation towards the anti-inflammatory IL-10 promoter and subsequently increased expression of IL-10 [54]. Treatment of HDAC 6 selective inhibitor Tubastatin A in a murine asthma model can reduce airway inflammation, airway remodeling, and airway hyperresponsiveness [55]. All these evidences indicate that HDAC isoforms play crucial roles
Name Application Clinical trial Reference Vorinostat(SAHA) T-cell lymphoma FDA approved [30] Belinostat(Beleodaq) T-cell Lymphoma FDA approved [31] Panobinostat(LBH-589) Multiple myeloma FDA approved [32] Resminostat(4SC-201) Advanced Solid Tumors Phase II [33] Givinostat(ITG2357) Multiple myeloma Phase II [34] Pracinostat(SB939) Myeloid leukemia Phase II [35] Abexinostat(PCI-24781) Lymphoma, or chronic lymphocytic leukemia Phase I [36] Entinostat(MS-275) Breast cancer Phase II [37] Mocetinostat(MGCD0103) Metastatic leiomyosarcoma Phase II [38] Tacedinaline(CI-994) Multiple myeloma and lung cancer Phase III [20] Ricolinostat(ACY-1215) Multiple myeloma Phase I/II [39] Chidamide(CS055) Solid tumor and non-small cell lung cancer CPDA approved [40] Romidepsin(FK288) T-Cell Lymphoma FDA approved [41] Valproic acid(VPA) Adenoid cystic carcinoma Phase I [42] Phenylbutyrate Recurrent malignant gliomas or
myelodysplastic syndrome
Phase I [43] AR-42 Myeloid leukemia Phase I [44] CUDC-101 Head and neck squamous cell carcinoma Phase I [45] Fimepinostat(CUDC-907) Lymphoma Phase I [46]
in inflammation. However, a remaining challenge is to develop selective inhibitors for the different HDAC isoenzymes, and to unravel the functions of these HDAC isoenzymes in specific disease models.
4. Design of HDACs antagonists
Most small molecular HDAC inhibitors were designed according to a general pharmacophore model that consists of three parts: (i) a zinc binding group (ZBG) to chelate the catalytic zinc ion; (ii) a linker to occupy the tunnel of the active site; (iii) a cap to close the entrance of the active site (Figure 1). In fact, this model for the HDAC pharmacophore composition is sufficiently powerful to build up the vast majority of HDAC inhibitors and is widely used since it was proposed by Jung in 1997 [56].
Figure 1. Chemical structure of representative hydroxamic acids (Vorinostat) and o-aminoanilides
(Entinostat).
So far, the most well-studied ZBGs are hydroxamic acids and o-aminoanilides. Studies on structure activity relationships (SAR) of ZBGs have shown that hydroxamic acid group mainly target on class I, II and IV HDACs, while the o-aminoanilines mainly target class I HDACs [57]. Further modification for o-aminoanilines demonstrated that a fluorine substitution in C-4 contributed to a better selectivity for HDAC 3, while an aromatic substitution in C-5 provided a loss in potency for HDAC 3 [6,58,59]. The linker also affect the selectivity of HDAC inhibitors. Inhibitors with a linear alkane linker and a hydroxamic acids zinc binding group are commonly non-selective among HDACs. In contrast, inhibitors with an aromatic linker or a substituted alkane linker and a hydroxamic acid ZBG commonly showed selectivity for HDAC 6 or/and HDAC 8 [60]. Inhibitors with an o-aminoaniline ZBG and a linear alkane linker displayed preference for HDAC 3 [61], while inhibitors with the same ZBG and an aromatic linker show
non-selectivity for class I HDACs. Also the cap groups influence the potency and selectivity of HDAC inhibition [62].
The flexibility in the design of the cap groups of HDAC inhibitors enable a new strategy to design and develop dual acting or multi-targeted HDAC inhibitors. Combination of appropriate ZBGs and linkers of HDAC inhibitors with pharmacophores of small molecule modulators of other targets provides hybrid molecules that target both HDAC and another protein of interest at the same time [63]. Combination of HDAC inhibitors with other inhibitors that target alternative cancer related mechanism has become a new trend to achieve synergistic effects in cancer drug discovery [64]. An example of this is CUDC-101 (Figure 2), which is a hybrid of Vorinostat and erlotinib with a nanomolar potency against HDACs, EGFR and human epidermal growth factor receptor 2 (HER2) simultaneously. This multi-targeted inhibitor is already in a phase I clinical trial to treat head and neck squamous cell carcinoma [45]. Another HDAC/PI3K dual inhibitor, CUDC-907 (Fimepinostat), is granted fast track designation by FDA to treat relapsed or refractory diffuse large B-cell lymphoma in phase I clinical trial [46]. More dual HDAC inhibitors, such as HDAC/BET inhibitors [65], HDAC/JAK inhibitors [66], are developed and provide synergistic anti-cancer activity, which indicates that development of dual HDAC inhibitors is an attractive therapeutic strategy for cancer treatment.
Figure 2. Chemical structure of CUDC-101.
Another way to make multi-targeted ligands is application of the novel proteolysis targeting chimera (PROTAC) technology. This technology implies linkage of an inhibitor of the target of interest to an E3 ubiquitin ligase ligand to trigger ubiquitination. The resulting ubiquitination of the target of interest triggers subsequent degradation [67]. The PROTACs are
heterobifunctional molecules, which consist of three parts: a ligand for binding the respective protein target, a ligand for recruiting an E3 ligase and a linker connecting these two ligands [69]. This strategy has recently been applied to HDACs [68]. In 2018, the first HDAC 6 directed PROTAC was developed by connecting a nonselective hydroxamic acid HDAC inhibitor to a cereblon (CRBN) ligand [70]. Later, a PROTAC targeting HDAC 1 and 2 was developed by tethering o-aminoanilide with a ligand for the von Hippel−Lindau E3 ligase [71]. This PROTAC-treatment of HCT116 cells with 10 μM concentration for 24 h led to degradation of HDAC 1 and HDAC 2. The new technology of PROTAC provides a novel approach to develop selective modulators of HDAC protein levels, which provides a conceptually novel approach for drug development.
Figure 3. Chemical structure of HDAC 6 degrader.
Scope of the thesis
The current achievements in epigenetic therapeutics, such as HDAC inhibitors, demonstrate their great potential and have fortified the quest for conceptually novel HDAC inhibitors. Although the roles of HDACs in many cellular pathways and functions have been elucidated, further studies are necessary to disclose their functions in specific disease models. Also, development of conceptually novel HDAC inhibitors holds potential to advance this field. Design of ligands according to the PROTAC-strategy provides opportunities to reduce the HDAC protein levels. Moreover, design of multi-targeted ligands provides opportunities to effectively interfere with signaling pathways involved in cell proliferation. The work described in this thesis aimed to apply such novel approaches in design and synthesis of small molecules
as HDAC antagonists. We also study their application in model systems for inflammatory airway diseases and cell proliferation in cancer.
In Chapter 2, we review the development and perspectives of selective HDAC 3 inhibitors, such as the role of HDAC 3 in inflammation and degenerative neurological diseases. Furthermore, we analyze structural difference between the active sites of HDAC 3 and HDAC 1/2 in order to support further development of HDAC 3 selective inhibitors. In addition, we summarized the currently known HDAC 3 selective inhibitors. Altogether, this provides a perspective for development of HDAC 3 inhibitors with improved selectivity and potency and their potential application in drug discovery projects.
In Chapter 3, we developed a series of Entinostat analogs and investigated their structure-activity relationship in inhibitory selectivity among HDAC 1, 2 and 3. Then, we studied their respective influence on gene transcription to facilitate drug discovery. Further cell based studies were done to explore the influence of synthesized HDAC inhibitors on the activity of the NF-κB pathway and pro- and anti-inflammation gene transcriptional levels in RAW264.7 macrophages.
In Chapter 4, a new technology, proteolysis targeting chimera (PROTACs), was applied to develop small molecules to degrade HDAC 3 in RAW264.7 cells. A series of class I HDAC degraders were synthesized by tethering o-aminoanilide-based class I HDAC inhibitors to pomalidomide as cereblon ligand. Western blot was employed to validate the degradation effect of these HDAC-PROTACs (HD-TACs) in cells. One of these HD-TACs showed promising degradation effects for HDAC 3 with a DC50 value of 0.32 µM. The pro- and anti-inflammatory
gene transcriptional levels in the PROTAC-treated cells were also investigated, but did not alter the same way as observed in biochemical experiments using siRNA. We found this was attributed to side-effect of cereblon ligand by downregulation of the NF-κB p65 subunit. In Chapter 5, we designed and synthesized a dual HDAC-MIF inhibitor by linking the pharmacophores of a HDAC inhibitor to a MIF inhibitor. Cell viability upon dual inhibitor treatment was examined among several non-small cell lung carcinoma (NSCLS) cell lines. H1650 and A549EGFR-/- proved sensitive to this HDAC-MIF dual inhibitor. Further study on the
promising potency of this inhibitor for the treatment of NSCLC. Western blot analysis showed that dual inhibitor facilitated cell apoptosis by blocking the AKT pathway.
In Chapter 6, we summarize the work presented in this thesis and discuss for further perspectives.
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