Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia

Cao, Fang; Townsend, Elizabeth; Karataş, Hacer; Xu, Jing; Li, Li; Lee, Shirley; Liu, Liu; Chen, Yong; Ouillette, Peter; Zhu, Jidong; Hess, Jay L.; Atadja, Peter; Lei, Ming; Qin, Zhaohui S.; Malek, Sami N.; Wang, Shaomeng; Dou, Yali

doi:10.1016/j.molcel.2013.12.001

Cited by 275 publications

(353 citation statements)

References 49 publications

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“…4). Seemingly, in some measure of conflict with some other reported results, 43 we find that the omission of WDR5 from assembled MLL/SET1 complexes is by no means completely inhibitory, relative to the activities of each of the full MLL/SET1-WRAD 2 complexes (Fig. 4A-C).…”

Section: Relative Merits Of the Win-motif Mimetic And Set-targeted Apcontrasting

confidence: 83%

“…showing specificity for MLL1 as well as the WDR5 omission experiments showing a lack of effect on the activity of all MLL/ SET1 family complexes other than MLL1 were all performed at a single relatively high complex concentration (500 nM) 43 and thus might have missed a concentration-dependent effect on WDR5 dependence, such as that observed for MLL1 (Fig. 4D).…”

Section: Discussionmentioning

confidence: 90%

“…The MLL1-WRAD 2 complex, however, is currently of greater interest as a drug development target, 43,55 so primary emphasis was placed on it in the course of the screening and profiling work.…”

Section: Discussionmentioning

confidence: 99%

“…4A, B) are strikingly different from those reported by Cao et al, in which omission of WDR5 has essentially no effect on the SET1A activity, while the MLL1 activity is nearly completely eliminated. 43 With regard to the points just discussed, it is worth noting the recent spate of successes in developing potent, SETtargeted, SAM-competitive inhibitors of EZH2 [56][57][58][59][60][61][62] and to also note that the MLL/SET1 family presents a number of features that parallel those of the EZHs. First, despite one group's catalysis of a gene repressive modification (EZH, H3K27 methylation) and the others catalysis of an activating one (MLL/ SET1, H3K4 methylation), the two groups share the same branch of the KMT phylogeny tree.…”

Section: Discussionmentioning

confidence: 99%

“…29,40 To date, most of the reported effort to pharmacologically target the MLL1 catalytic activity has centered on attempts to disrupt the MLL1-WDR5 interaction by means of Win-motifmimicking peptides and small-molecule peptidomimetics. [39][40][41][42][43] A parallel strategy aimed at disrupting the Menin-MLL1 interaction of oncogenic MLL1 fusion proteins and/or wild-type MLL1 [44][45][46] appears to be bearing fruit in the form of efficacy in mouse models of MLL and primary samples from MLL patients 47 and in mouse xenograft models of castration-resistant prostate cancer. 48 However, for reasons that we will discuss, we have chosen to pursue an assay development strategy that instead focuses on optimizing conditions for the discovery and characterization of inhibitors of MLL/SET1 catalysis per se, that is, inhibitors more likely to bind and affect the SET domain.…”

Section: Introductionmentioning

confidence: 99%

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Development and Use of Assay Conditions Suited to Screening for and Profiling of SET-Domain-Targeted Inhibitors of the MLL/SET1 Family of Lysine Methyltransferases

Ferry

Smith

Denney

et al. 2015

ASSAY and Drug Development Technologies

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Methylation of histone H3 lysine-4 (H3K4) is an important, regulatory, epigenetic post-translational modification associated with actively transcribed genes. In humans, the principal mediators of this modification are part of the MLL/SET1 family of methyltransferases, which comprises six members, MLLs1-4 and SET1A/SET1B. Aberrations in the structure, expression, and regulation of these enzymes are implicated in various disease states, making them important potential targets for drug discovery, particularly for oncology indications. The MLL/SET1 family members are most enzymatically active when part of a ''core complex,'' the catalytic SET-domain-containing subunits bound to a subcomplex consisting of the proteins WDR5, RbBP5, Ash2L and a homodimer of DPY-30 (WRAD 2 ). The necessity of MLL/SET1 members to bind WRAD 2 for full activity is the basis of a particular drug development strategy, which seeks to disrupt the interaction between the MLL/SET1 subunits and WDR5. This strategy is not without its theoretical and practical drawbacks, some of which relate to the ease with which complexes of Escherichia coli-expressed MLL/SET1 and WRAD 2 fall apart. As an alternative strategy, we explore ways to stabilize the complex, focusing on the use of an excess of WRAD 2 to drive the binding equilibria toward complex formation while maintaining low concentrations of the catalytic subunits. The purpose of this approach is to seek inhibitors that bind the SET domain, an approach proven successful with the related, but inherently more stable, enhancer of zeste homolog 2 (EZH2) complex.

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Section: Relative Merits Of the Win-motif Mimetic And Set-targeted Apcontrasting

confidence: 83%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development and Use of Assay Conditions Suited to Screening for and Profiling of SET-Domain-Targeted Inhibitors of the MLL/SET1 Family of Lysine Methyltransferases

Ferry

Smith

Denney

et al. 2015

ASSAY and Drug Development Technologies

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Somatic cancer mutations in the MLL1 histone methyltransferase modulate its enzymatic activity and dependence on the WDR5/RBBP5/ASH2L complex

2017

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Somatic missense mutations in the mixed lineage leukemia 1 (MLL1) histone H3K4 methyltransferase are often observed in cancers. MLL1 forms a complex with WDR5, RBBP5, and ASH2L (WRA) which stimulates its activity. The MM‐102 compound prevents the interaction between MLL1 and WDR5 and functions as an MLL1 inhibitor. We have studied the effects of four cancer mutations in the catalytic SET domain of MLL1 on the enzymatic activity of MLL1 and MLL1–WRA complexes. In addition, we studied the interaction of the MLL1 mutants with the WRA proteins and inhibition of MLL1–WRA complexes by MM‐102. All four investigated mutations had strong effects on the activity of MLL1. R3903H was inactive and S3865F showed reduced activity both alone and in complex with WRA, but its activity was stimulated by the WRA complex. By contrast, R3864C and R3841W were both more active than wild‐type MLL1, but still less active than the wild‐type MLL1–WRA complex. Both mutants were not stimulated by complex formation with WRA, although no differences in the interaction with the complex proteins were observed. These results indicate that both mutants are in an active conformation even in the absence of the WRA complex and their normal control of activity by the WRA complex is altered. In agreement with this observation, the activity of R3864C and R3841W was not reduced by addition of the MM‐102 inhibitor. We show that different cancer mutations in MLL1 lead to a loss or increase in activity, illustrating the complex and tumor‐specific role of MLL1 in carcinogenesis. Our data exemplify that biochemical investigations of somatic tumor mutations are required to decipher their pathological role. Moreover, our data indicate that MM‐102 may not be used as an MLL1 inhibitor if the R3864C and R3841W mutations are present. More generally, the efficacy of any enzyme inhibitor must be experimentally confirmed for mutant enzymes before an application can be considered.

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