Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target

Lechner, Severin; Malgapo, Martin Ian P.; Grätz, Christian; Steimbach, Raphael R.; Baron, Agnes; Rüther, Patrick; Nadal, Simon; Stumpf, Carmen; Loos, Christina; Ku, Xin; Prokofeva, Polina; Lautenbacher, Ludwig; Heimburg, Tino; Würf, Vivian; Meng, Chen; Wilhelm, Mathias; Sippl, Wolfgang; Kleigrewe, Karin; Pauling, Josch; Kramer, Karl; Miller, Aubry K.; Pfaffl, Michael W.; Linder, Maurine E.; Küster, Bernhard; Médard, Guillaume

doi:10.1038/s41589-022-01015-5

Cited by 67 publications

(73 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unfortunately, the currently in use HDAC-selective inhibitors have off-target effects highlighting the need to improve the potency and selectivity of the HDAC inhibitors. This purpose could be achieved by HDAC-specific inhibitor design according to their unique structures [ 131 , 132 ]. The identification of agents being capable of binding with individual HDACs could be helpful in the introduction of new anti-melanoma therapies.…”

Section: Role Of Epigenetic In Melanoma Development and Pathogenesismentioning

confidence: 99%

Current understanding of epigenetics role in melanoma treatment and resistance

et al. 2022

View full text Add to dashboard Cite

Melanoma is the most aggressive form of skin cancer resulting from genetic mutations in melanocytes. Several factors have been considered to be involved in melanoma progression, including genetic alteration, processes of damaged DNA repair, and changes in mechanisms of cell growth and proliferation. Epigenetics is the other factor with a crucial role in melanoma development. Epigenetic changes have become novel targets for treating patients suffering from melanoma. These changes can alter the expression of microRNAs and their interaction with target genes, which involves cell growth, differentiation, or even death. Given these circumstances, we conducted the present review to discuss the melanoma risk factors and represent the current knowledge about the factors related to its etiopathogenesis. Moreover, various epigenetic pathways, which are involved in melanoma progression, treatment, and chemo-resistance, as well as employed epigenetic factors as a solution to the problems, will be discussed in detail.

show abstract

Section: Role Of Epigenetic In Melanoma Development and Pathogenesismentioning

confidence: 99%

Current understanding of epigenetics role in melanoma treatment and resistance

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Up to now, no HDAC10i that fulfills the requirements of a selective chemical probe has been described . While HDAC10 inhibitors with selectivity over the Class I isozymes are known, the primary challenge lies in achieving selectivity over the other Class IIB member, HDAC6. ,− A good example for this is tubastatin A ( 1 ), a well-known HDAC6i, which is an even more potent HDAC10 binder (Figure , far left box). , We previously showed that an electrostatic interaction between the tertiary amine of the tetrahydro-γ-carboline ring of 1 and the E274 gatekeeper residue in HDAC10 is responsible for its strong binding. , The gatekeeper residue is unique to HDAC10, and its negative charge provides an attractive interaction with positively charged polyamines (or HDAC10 inhibitors) within HDAC10’s binding site. Ring-opened tubastatin A derivative DKFZ‑480 ( 2 ) makes a direct hydrogen bond to E274, which results in enhanced binding affinity.…”

Section: Introductionmentioning

confidence: 99%

Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout

et al. 2022

Self Cite

View full text Add to dashboard Cite

We report the first well-characterized selective chemical probe for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inserted an amino group (“aza-scan”) into the hexyl linker moiety of the approved drug Vorinostat (SAHA). This one-atom replacement (C→N) transformed SAHA from an unselective pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization of the aza-SAHA structure yielded the HDAC10 chemical probe DKFZ‑748, with potency and selectivity demonstrated by cellular and biochemical target engagement, as well as thermal shift assays. Cocrystal structures of our aza-SAHA derivatives with HDAC10 provide a structural rationale for potency, and chemoproteomic profiling confirmed exquisite cellular HDAC10-selectivity of DKFZ‑748 across the target landscape of HDAC drugs. Treatment of cells with DKFZ‑748, followed by quantification of selected polyamines, validated for the first time the suspected cellular function of HDAC10 as a polyamine deacetylase. Finally, in a polyamine-limiting in vitro tumor model, DKFZ‑748 showed dose-dependent growth inhibition of HeLa cells. We expect DKFZ‑748 and related probes to enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines in both physiological and pathological settings.

show abstract

“…However, KO of HDAC6 barely altered the response of Ramos cells towards ACY-1215, revealing a very narrow window of specific targeting (Figure 3G, Supplemental Figure 6B). This underlines that M-100 has improved specificity for HDAC6 compared to ACY-1215 whose off-targets were recently described in detail (38).…”

Section: Hdac6 Inhibition Results In Apoptosis Of Human B-cell Lympho...mentioning

confidence: 59%

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

Winkler

Mägdefrau

Kleemann

et al. 2021

Preprint

View full text Add to dashboard Cite

Overexpression of oncogenic MYC is the hallmark of many lymphomas and is related to a poor prognosis. Although MYC is a potential cancer driver, therapeutic targeting is still challenging. Here, we report that histone deacetylase 6 (HDAC6) inhibition using the novel inhibitor Marbostat-100 (M-100) specifically alters protein-protein interactions in MYC-dependent cancer cells and targets MYC for proteasomal degradation. Subsequently, massive apoptosis is induced in MYC-overexpressing B-cell lymphoma cells after M-100 treatment. Besides, the application of M-100 prevents lymphoma formation in Eμ-Myc transgenic mice and efficiently slows down tumor growth in already manifested lymphomas. Moreover, M-100 exclusively targets MYC-dependent tumor cells with little or no side effects on non-tumor cells and tissues. HDAC6 inhibition results in pleiotropic cellular effects, such as hyperacetylation of Tubulin. We propose a mechanism where the heat-shock protein DNAJA3 associates with acetylated Tubulin to control MYC turnover in malignant cells. Our data show a new mechanism how HDAC6 inhibition targets oncogenic MYC in lymphomas and demonstrate a beneficial role of HDAC6 inhibition in MYC-dependent B-cell lymphoma.

show abstract

Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target

Cited by 67 publications

References 62 publications

Current understanding of epigenetics role in melanoma treatment and resistance

Current understanding of epigenetics role in melanoma treatment and resistance

Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

Contact Info

Product

Resources

About