Peptidomimetics for Targeting Protein–Protein Interactions between DOT1L and MLL Oncofusion Proteins AF9 and ENL

Du, Lei; Grigsby, Sierrah; Yao, Aihong; Chang, Yuan‐Jen; Johnson, Glen E.; Sun, Haiying; Nikolovska‐Coleska, Zaneta

doi:10.1021/acsmedchemlett.8b00175

Cited by 21 publications

(34 citation statements)

References 19 publications

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“…We have successfully developed the first class of peptidomimetics that target PPIs between DOT1L and MLL onco-fusion proteins, AF9 and ENL, based on the 10mer DOT1L peptide [ 40 ]. The findings of this study provide further evidence validating the rationale for a novel promising strategy that disrupts interactions between DOT1L and AF9 in MLL fusion protein-associated leukemia.…”

Section: Discussionmentioning

confidence: 99%

“…This study further confirmed that DOT1L recruitment by AF9 is necessary for MLL-AF9 mediated colony-formation and leukemic transformation. Recently we reported a class of peptidomimetics based on the 10-mer DOT1L binding peptide, providing a proof-of-concept for the development of nonpeptidic compounds to inhibit DOT1L activity by targeting its interaction with MLL-oncofusion proteins, AF9 and ENL [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

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Elucidating the Importance of DOT1L Recruitment in MLL-AF9 Leukemia and Hematopoiesis

Grigsby

Friedman

Chase

et al. 2021

Cancers

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MLL1 (KMT2a) gene rearrangements underlie the pathogenesis of aggressive MLL-driven acute leukemia. AF9, one of the most common MLL-fusion partners, recruits the histone H3K79 methyltransferase DOT1L to MLL target genes, constitutively activating transcription of pro-leukemic targets. DOT1L has emerged as a therapeutic target in patients with MLL-driven leukemia. However, global DOT1L enzymatic inhibition may lead to off-target toxicities in non-leukemic cells that could decrease the therapeutic index of DOT1L inhibitors. To bypass this problem, we developed a novel approach targeting specific protein-protein interactions (PPIs) that mediate DOT1L recruitment to MLL target genes, and compared the effects of enzymatic and PPIs inhibition on leukemic and non-leukemic hematopoiesis. MLL-AF9 cell lines were engineered to carry mutant DOT1L constructs with a defective AF9 interaction site or lacking enzymatic activity. In cell lines expressing a DOT1L mutant with defective AF9 binding, we observed complete disruption of DOT1L recruitment to critical target genes and inhibition of leukemic cell growth. To evaluate the overall impact of DOT1L loss in non-leukemic hematopoiesis, we first assessed the impact of acute Dot1l inactivation in adult mouse bone marrow. We observed a rapid reduction in myeloid progenitor cell numbers within 7 days, followed by a loss of long-term hematopoietic stem cells. Furthermore, WT and PPI-deficient DOT1L mutants but not an enzymatically inactive DOT1L mutant were able to rescue sustained hematopoiesis. These data show that the AF9-DOT1L interaction is dispensable in non-leukemic hematopoiesis. Our findings support targeting of the MLL-AF9—DOT1L interaction as a promising therapeutic strategy that is selectively toxic to MLL-driven leukemic cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Elucidating the Importance of DOT1L Recruitment in MLL-AF9 Leukemia and Hematopoiesis

Grigsby

Friedman

Chase

et al. 2021

Cancers

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“…Medicinal chemistry optimization yielded a series of 7-mer peptidomimetic compounds 21 and 28 (Fig. 12 e) against the interaction between AF9/ENL and DOT1L with IC 50 values as low as 57 nM [ 197 ]…”

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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“…In recent years, new compounds with different mechanisms of action have been developed. Unlike the first class of DOT1L inhibitors, mimetic peptide molecules such as compound (8), shown in Figure 3, do not determine total inhibition of DOT1L activity, but bind AF9/ENL, thus blocking recruitment of DOT1L to MLL target genes and reducing levels of HOAX9 [110].…”

Section: Dot1l Inhibitorsmentioning

confidence: 99%

DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment

2019

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Methylation of histone 3 at lysine 79 (H3K79) is one of the principal mechanisms involved in gene expression. The histone methyltransferase DOT1L, which mono-, di-and trimethylates H3K79 using S-adenosyl-L-methionine as a co-factor, is involved in cell development, cell cycle progression, and DNA damage repair. However, changes in normal expression levels of this enzyme are found in prostate, breast, and ovarian cancer. High levels of H3K79me are also detected in acute myeloid leukaemia patients bearing MLL rearrangements (MLL-r). MLL translocations are found in approximately 80% of paediatric patients, leading to poor prognosis. DOT1L is recruited on DNA and induces hyperexpression of HOXA9 and MEIS1. Based on these findings, selective drugs have been developed to induce apoptosis in MLL-r leukaemia cells by specifically inhibiting DOT1L. The most potent DOT1L inhibitor pinometostat has been investigated in Phase I clinical trials for treatment of paediatric and adult patients with MLL-driven leukaemia, showing promising results. ARTICLE HISTORY

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Peptidomimetics for Targeting Protein–Protein Interactions between DOT1L and MLL Oncofusion Proteins AF9 and ENL

Cited by 21 publications

References 19 publications

Elucidating the Importance of DOT1L Recruitment in MLL-AF9 Leukemia and Hematopoiesis

Elucidating the Importance of DOT1L Recruitment in MLL-AF9 Leukemia and Hematopoiesis

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

DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment

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