Discovery of an MLLT1/3 YEATS Domain Chemical Probe

Moustakim, Moses; Christott, Thomas; Monteiro, Octovia; Bennett, James M.; Giroud, Charline; Ward, Jennifer; Rogers, Catherine; Smith, Paul; Panagakou, Ioanna; Diaz-Saez, L.; Felce, Suet Ling; Gamble, Vicki; Gileadi, C.; Halidi, Nadia; Heidenreich, David; Chaikuad, A.; Knapp, S.; Huber, Kilian; Farnie, Gillian; Heer, Jag; Manevski, Nenad; Poda, Gennady; Al‐awar, Rima; Dixon, Darren J.; Brennan, P.E.; Fedorov, Oleg

doi:10.1002/anie.201810617

Cited by 67 publications

(80 citation statements)

References 29 publications

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“…Other BRDs have less druggable binding sites making the development of high-affinity chemical probes challenging. There are now also structurally diverse Kac-binding domains called YEATs domains that have recently been targeted by small molecules and fragments 68,69 . It is therefore likely that the arsenal of chemical probes for these reader domains will continue to grow in the future.…”

Section: Discussionmentioning

confidence: 99%

A chemical toolbox for the study of bromodomains and epigenetic signaling

Heidenreich

Zhou

et al. 2019

Nat Commun

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Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMO scan and demonstrate the utility of the set identifying roles of BRDs in cellular processes and potential translational applications. For instance, we discovered crosstalk between histone acetylation and the glycolytic pathway resulting in a vulnerability of breast cancer cell lines under conditions of glucose deprivation or GLUT1 inhibition to inhibition of BRPF2/3 BRDs. This chemical probe-set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.

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Section: Discussionmentioning

confidence: 99%

A chemical toolbox for the study of bromodomains and epigenetic signaling

Heidenreich

Zhou

et al. 2019

Nat Commun

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“…Peptidic and small molecule inhibitors of ENL YEATS have been reported [ 200 – 202 ]. Peptidic inhibitors XL-07i and XL-13m (Fig.…”

Section: Ppis Involving Mll1 Fusion Proteinsmentioning

confidence: 99%

“…A structure-based approach led to the discovery of a series of benzimidazole inhibitors of ENL YEATS, with SGC-iMLLT (compound 92, Fig. 13 h) exhibiting an IC 50 of 260 nM [ 200 ]. The inhibitor was found to suppress expression of leukemia relevant genes such as Myc.…”

Section: Ppis Involving Mll1 Fusion Proteinsmentioning

confidence: 99%

Structure, function and inhibition of critical protein–protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins

Song

2021

J Hematol Oncol

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Mixed lineage leukemia 1 (MLL1, also known as MLL or KMT2A) is an important transcription factor and histone-H3 lysine-4 (H3K4) methyltransferase. It is a master regulator for transcription of important genes (e.g., Hox genes) for embryonic development and hematopoiesis. However, it is largely dispensable in matured cells. Dysregulation of MLL1 leads to overexpression of certain Hox genes and eventually leukemia initiation. Chromosome translocations involving MLL1 cause ~ 75% of acute leukemia in infants and 5–10% in children and adults with a poor prognosis. Targeted therapeutics against oncogenic fusion MLL1 (onco-MLL1) are therefore needed. Onco-MLL1 consists of the N-terminal DNA-interacting domains of MLL1 fused with one of > 70 fusion partners, among which transcription cofactors AF4, AF9 and its paralog ENL, and ELL are the most frequent. Wild-type (WT)- and onco-MLL1 involve numerous protein–protein interactions (PPI), which play critical roles in regulating gene expression in normal physiology and leukemia. Moreover, WT-MLL1 has been found to be essential for MLL1-rearranged (MLL1-r) leukemia. Rigorous studies of such PPIs have been performed and much progress has been achieved in understanding their structures, structure–function relationships and the mechanisms for activating gene transcription as well as leukemic transformation. Inhibition of several critical PPIs by peptides, peptidomimetic or small-molecule compounds has been explored as a therapeutic approach for MLL1-r leukemia. This review summarizes the biological functions, biochemistry, structure and inhibition of the critical PPIs involving MLL1 and its fusion partner proteins. In addition, challenges and perspectives of drug discovery targeting these PPIs for the treatment of MLL1-r leukemia are discussed.

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“…[101] Several peptidic [102] and small-molecule inhibitors [103,104] of the AF9/ENL YEATS domains have been reported with some demonstrating activity in cells. [105] Indeed, an interesting chemical biology approach enabled the discovery of novel cell based YEATS domain inhibitors [106] by coupling cellular thermal shift assay (CETSA) [107] with luminescence. [108] These reports hold great promise for future modulation of acetyllysine readers beyond the bromodomain.…”

Section: Other Readersmentioning

confidence: 99%

“…Similarly, the YEATS domain containing ENL protein, a common MLL fusion partner in leukaemias, has been shown to recruit RNA PolII to oncogenes via recognition of H3K27Ac and H3K9Ac [101] . Several peptidic [102] and small‐molecule inhibitors [103,104] of the AF9/ENL YEATS domains have been reported with some demonstrating activity in cells [105] . Indeed, an interesting chemical biology approach enabled the discovery of novel cell based YEATS domain inhibitors [106] by coupling cellular thermal shift assay (CETSA) [107] with luminescence [108] .…”

Section: Lysine Post‐translational Modificationsmentioning

confidence: 99%

Advances and Opportunities in Epigenetic Chemical Biology

2020

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The study of epigenetics has greatly benefited from the development and application of various chemical biology approaches. In this review, we highlight the key targets for modulation and recent methods developed to enact such modulation. We discuss various chemical biology techniques to study DNA methylation and the post-translational modification of histones as well as their effect on gene expression. Additionally , we address the wealth of protein synthesis approaches to yield histones and nucleosomes bearing epigenetic modifications. Throughout, we highlight targets that present opportunities for the chemical biology community, as well as exciting new approaches that will provide additional insight into the roles of epigenetic marks.

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Discovery of an MLLT1/3 YEATS Domain Chemical Probe

Cited by 67 publications

References 29 publications

A chemical toolbox for the study of bromodomains and epigenetic signaling

A chemical toolbox for the study of bromodomains and epigenetic signaling

Structure, function and inhibition of critical protein–protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins

Advances and Opportunities in Epigenetic Chemical Biology

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