Pharmacological Modulation of the Crosstalk between Aberrant Janus Kinase Signaling and Epigenetic Modifiers of the Histone Deacetylase Family to Treat Cancer

Mustafa, Al-Hassan M.; Krämer, Oliver H.

doi:10.1124/pharmrev.122.000612

Cited by 17 publications

(16 citation statements)

References 309 publications

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“…The low nanomolar inhibitory activity of these agents encouraged us to test them in leukemic cells. Since HDACi are considered for the treatment of myeloproliferative neoplasms (MPNs) [2, 33], we chose HEL erythroleukemia cells as testbed to analyze cellular effects of our new HDACi. We treated these cells with KH9, KH16, and KH29 and assessed early apoptosis (annexin-V positivity) and late apoptosis (annexin-V/PI positivity) by flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

“…The FDA has approved HDACi as treatment option for cutaneous T cell lymphoma and myeloma [1,4,5]. MPNs mainly comprise polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukemia (CML) [2]. Median survival rates in patients affected by MPNs range from 19.8 years in patients with ET to 13.5 years in patients diagnosed with PV and 5.9 years in patients with PMF.…”

Section: Discussionmentioning

confidence: 99%

“…18 mammalian HDACs are classified into four classes, based on their homology to yeast HDACs. Class I HDACs comprise HDAC1,-2,-3,-8, class II is divided into IIA being HDAC4,-5,-7,-9 and class IIB being HDAC6,-10, and class IV contains only HDAC11, which has properties of classes I and II [1, 2]. The HDAC classes I, II, and IV use Zn 2+ as a cofactor and the class III HDACs SIRT1-7 utilize NAD + as a cofactor [2, 3].…”

Section: Introductionmentioning

confidence: 99%

“…HDACi against Zn 2+ -dependent HDACs have been approved by the U.S. food-and-drug administration (FDA) for the therapy of human blood tumors [1,4,5]. This was preceded by the use of weakly active, millimolar fatty acid HDACi in compassionate protocols in the last century [2]. The micromolar hydroxamic acid vorinostat (SAHA) was the first clinically approved HDACi.…”

Section: Introductionmentioning

confidence: 99%

“…This encourages the synthesis of HDACi with selectivity for these enzymes. Beyond high activity against tumor cells, selective HDACi are expected to have less side-effects than pan-HDACi [2]. HDACi with the benzamide group as a molecular warhead to complex Zn 2+ can have remarkable class I HDAC selectivity but lack the low nanomolar activities of depsipeptides and hydroxamic acids [6,7,10,11].…”

Section: Introductionmentioning

confidence: 99%

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Novel hydroxamic acid derivative induces apoptosis and constrains autophagy in leukemic cells

Fischer

Mustafa

Hausmann

et al. 2023

Preprint

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Introduction: Posttranslational modification of proteins by reversible acetylation regulates key biological processes. Histone deacetylases (HDACs) catalyze protein deacetylation and are frequently dysregulated in tumors. This has spurred the development of HDAC inhibitors (HDACi). Such epigenetic drugs modulate protein acetylation, eliminate tumor cells, and are approved for the treatment of blood cancers. Objectives: We aimed to identify novel, nanomolar HDACi with increased potency over existing agents and selectivity for the cancer-relevant class I HDACs (HDAC1/-2/-3/-8). Moreover, we wanted to define how such drugs control the apoptosis-autophagy interplay. As test systems, we used human leukemic cells and embryonic kidney-derived cells. Methods: We synthesized novel pyrimidine-hydroxamic acid HDACi (KH9/KH16/KH29) and performed in vitro activity assays and molecular modeling of their direct binding to HDACs. We analyzed how these HDACi affect leukemic cell fate, acetylation, and protein expression with flow cytometry and immunoblot. The publicly available DepMap database of CRISPR-Cas9 screenings was used to determine sensitivity factors across human leukemic cells. Results: Novel HDACi show nanomolar activity against class I HDACs. These agents are superior to the clinically used hydroxamic acid HDACi vorinostat. Within the KH-series of compounds, KH16 (yanostat) is the most effective inhibitor of HDAC3 (IC50 = 6 nM) and the most potent inducer of apoptosis (IC50 = 110 nM; p<0.0001) in leukemic cells. KH16 though spares embryonic kidney-derived cells. Global data analyses of knockout screenings verify that HDAC3 is a dependency factor in human blood cancer cells of different lineages, independent of mutations in the tumor suppressor p53. KH16 alters pro- and anti-apoptotic protein expression, stalls cell cycle progression, and induces a caspase-dependent processing of the autophagy proteins ULK1 and p62. Conclusion: These data reveal that HDACs are required to stabilize autophagy proteins through a suppression of apoptosis in leukemic cells. HDAC3 appears as a valid anti-cancer target for pharmacological intervention.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel hydroxamic acid derivative induces apoptosis and constrains autophagy in leukemic cells

Fischer

Mustafa

Hausmann

et al. 2023

Preprint

Self Cite

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Pharmacological degradation of ATR induces antiproliferative DNA replication stress in leukemic cells

Kansy,

Ashry,

Mustafa

et al. 2024

Molecular Oncology

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Mammalian cells replicate ~ 3 × 109 base pairs per cell cycle. One of the key molecules that slows down the cell cycle and prevents excessive DNA damage upon DNA replication stress is the checkpoint kinase ataxia‐telangiectasia‐and‐RAD3‐related (ATR). Proteolysis‐targeting‐chimeras (PROTACs) are an innovative pharmacological invention to molecularly dissect, biologically understand, and therapeutically assess catalytic and non‐catalytic functions of enzymes. This work defines the first‐in‐class ATR PROTAC, Abd110/Ramotac‐1. It is derived from the ATR inhibitor VE‐821 and recruits the E3 ubiquitin‐ligase component cereblon to ATR. Abd110 eliminates ATR rapidly in human leukemic cells. This mechanism provokes DNA replication catastrophe and augments anti‐leukemic effects of the clinically used ribonucleotide reductase‐2 inhibitor hydroxyurea. Moreover, Abd110 is more effective than VE‐821 against human primary leukemic cells but spares normal primary immune cells. CRISPR‐Cas9 screens show that ATR is a dependency factor in 116 myeloid and lymphoid leukemia cells. Treatment of wild‐type but not of cereblon knockout cells with Abd110 stalls their proliferation which verifies that ATR elimination is the primary mechanism of Abd110. Altogether, our findings demonstrate specific anti‐leukemic effects of an ATR PROTAC.

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Design, synthesis, and biological characterization of proteolysis targeting chimera (PROTACs) for the ataxia telangiectasia and RAD3-related (ATR) kinase

Alfayomy,

Ashry,

Kansy

et al. 2024

European Journal of Medicinal Chemistry

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Pharmacological Modulation of the Crosstalk between Aberrant Janus Kinase Signaling and Epigenetic Modifiers of the Histone Deacetylase Family to Treat Cancer

Cited by 17 publications

References 309 publications

Novel hydroxamic acid derivative induces apoptosis and constrains autophagy in leukemic cells

Novel hydroxamic acid derivative induces apoptosis and constrains autophagy in leukemic cells

Pharmacological degradation of ATR induces antiproliferative DNA replication stress in leukemic cells

Design, synthesis, and biological characterization of proteolysis targeting chimera (PROTACs) for the ataxia telangiectasia and RAD3-related (ATR) kinase

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