Discovery of the First-in-Class Dual Histone Deacetylase–Proteasome Inhibitor

Bhatia, Sanil; Krieger, Viktoria; Groll, M.; Osko, J.D.; Reßing, Nina; Ahlert, Heinz; Borkhardt, Arndt; Kurz, Thomas; Christianson, D.W.; Hauer, Julia; Hansen, Finn K.

doi:10.1021/acs.jmedchem.8b01487

Cited by 63 publications

(67 citation statements)

References 39 publications

(73 reference statements)

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“…The amide group of SAHA forms water-mediated hydrogen bonds to Ser150 and the zinc ligand His232. Similar hydrogen-bond interactions are observed to the corresponding residues Ser531 and His614 in several HDAC6 CD2inhibitor complexes Hai & Christianson, 2016;Porter et al, 2017;Bhatia et al, 2018;Mackwitz et al, 2018). The benzophenone carbonyl group forms a hydrogen bond to a water molecule, which in turn forms hydrogen bonds to Asp79 and Ser81.…”

Section: Crystal Structure Of the K330l Hdac6 Cd1-saha-bpyne Complexsupporting

confidence: 58%

“…Thus, X-ray crystallographic studies of HDAC6 CD1 and CD2 have relied on the zebrafish enzyme as a surrogate for the human enzyme. More than 50 structures of zebrafish HDAC6 CD2-inhibitor complexes have since appeared in the literature Bhatia et al, 2018;Mackwitz et al, 2018;Porter et al, 2017;Porter, Osko et al, 2018;Porter, Shen et al, 2018;Porter, Wagner et al, 2018;Shen et al, 2020). In contrast, only seven additional crystal structures of zebrafish HDAC6 CD1inhibitor complexes have since been reported (Osko & Christianson, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Binding of inhibitors to active-site mutants of CD1, the enigmatic catalytic domain of histone deacetylase 6

Osko

Christianson

2020

Acta Cryst Sect F

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The zinc hydrolase histone deacetylase 6 (HDAC6) is unique among vertebrate deacetylases in that it contains two catalytic domains, designated CD1 and CD2. Both domains are fully functional as lysine deacetylases in vitro. However, the in vivo function of only the CD2 domain is well defined, whereas that of the CD1 domain is more enigmatic. Three X-ray crystal structures of HDAC6 CD1–inhibitor complexes are now reported to broaden the understanding of affinity determinants in the active site. Notably, cocrystallization with inhibitors was facilitated by using active-site mutants of zebrafish HDAC6 CD1. The first mutant studied, H82F/F202Y HDAC6 CD1, was designed to mimic the active site of human HDAC6 CD1. The structure of its complex with trichostatin A was generally identical to that with the wild-type zebrafish enzyme. The second mutant studied, K330L HDAC6 CD1, was prepared to mimic the active site of HDAC6 CD2. It has previously been demonstrated that this substitution does not perturb inhibitor binding conformations in HDAC6 CD1; here, this mutant facilitated cocrystallization with derivatives of the cancer chemotherapy drug suberoylanilide hydroxamic acid (SAHA). These crystal structures allow the mapping of inhibitor-binding regions in the outer active-site cleft, where one HDAC isozyme typically differs from another. It is expected that these structures will help to guide the structure-based design of inhibitors with selectivity against HDAC6 CD1, which in turn will enable new chemical biology approaches to probe its cellular function.

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Section: Crystal Structure Of the K330l Hdac6 Cd1-saha-bpyne Complexsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Binding of inhibitors to active-site mutants of CD1, the enigmatic catalytic domain of histone deacetylase 6

Osko

Christianson

2020

Acta Cryst Sect F

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“…Another HDAC6 inhibitor, WT161, promotes the accumulation of acetylated tubulin and overcomes BTZ resistance to promote multiple myeloma (MM) cell death (Hideshima et al, 2016). RTS-V5, a dual inhibitor that targets HDAC6 and the 20S subunit of the proteasome, also possesses potent and selective anti-tumor activity in leukemia and MM cell lines (Bhatia et al, 2018).…”

Section: Proteasome-dependent Degradationmentioning

confidence: 99%

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

Guo

Tian

Zhu

2020

Front. Cell Dev. Biol.

159

120

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Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units of chromatin. The fifth amino group (N ε) of histone lysine residues is a common site for post-translational modifications (PTMs), and of these, acetylation is the second most common. Histone acetylation is modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), and is involved in the regulation of gene expression. Over the past two decades, numerous studies characterizing HDACs and HDAC inhibitors (HDACi) have provided novel and exciting insights concerning their underlying biological mechanisms and potential anti-cancer treatments. In this review, we detail the diverse structures of HDACs and their underlying biological functions, including transcriptional regulation, metabolism, angiogenesis, DNA damage response, cell cycle, apoptosis, protein degradation, immunity and other several physiological processes. We also highlight potential avenues to use HDACi as novel, precision cancer treatments.

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“…The CellTiter-Glo luminescent cell viability assay (Promega, Madison, USA) was used for the proliferation activity assay following the manufacturer's instructions 37 . HUVECs in the logarithmic growth phase were collected and seeded in 384-well plates (1000 cells per well) with ECM basal medium containing 2% FBS.…”

Section: Methodsmentioning

confidence: 99%

Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Yao

Liu

Zhao

et al. 2020

Acta Pharmaceutica Sinica B

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Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure–activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFR β simultaneously in vitro . Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.

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Discovery of the First-in-Class Dual Histone Deacetylase–Proteasome Inhibitor

Cited by 63 publications

References 39 publications

Binding of inhibitors to active-site mutants of CD1, the enigmatic catalytic domain of histone deacetylase 6

Binding of inhibitors to active-site mutants of CD1, the enigmatic catalytic domain of histone deacetylase 6

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

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