Design, Synthesis, and Biological Evaluations of DOT1L Peptide Mimetics Targeting the Protein–Protein Interactions between DOT1L and MLL-AF9/MLL-ENL

Abstract

On the basis of a previously identified DOT1L peptide mimetic (compound 3), a series of novel peptide mimetics were designed and synthesized. These compounds can potently bind to AF9 and ENL either in cell-free binding assays or in leukemia cells, and selectively inhibit the growth of leukemia cells containing mixed lineage leukemia (MLL) fusion proteins. The most potent compound 12 exhibited comparable anticancer cellular activities to those of EPZ5676, a clinical stage enzymatic inhibitor of DOT1L in several leukemia cell lines containing MLL fusion proteins. Mechanism studies for compound 12 indicated that it did not affect the global methylation of H3K79 catalyzed by DOT1L but could effectively suppress the methylation of H3K79 at MLL fusion proteins targeted genes and inhibit the expressions of these genes. Our studies thus demonstrated that inhibiting the protein–protein interactions between DOT1L and MLL fusion proteins is a potentially effective strategy for the treatment of MLL rearranged leukemias.

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development

“…Likewise, targeting interactions between KMTA2 fusion partners and DOT1L emerged as a valid strategy against KMT2A r leukemia. DOT1L peptide mimetics and/or small molecule inhibitors disrupting interactions between DOT1L and AF9/AF10/ENL are currently under investigation ( Wu et al, 2021 ; Yi and Ge, 2022 ; Yuan et al, 2022 ). For example, a DOT1L peptide mimetic was synthesized to target DOT1L and AF9/ENL, and its use supressed growth of non-AMKL leukemic cell lines harboring KMT2A r ( Yuan et al, 2022 ).…”

“…DOT1L peptide mimetics and/or small molecule inhibitors disrupting interactions between DOT1L and AF9/AF10/ENL are currently under investigation ( Wu et al, 2021 ; Yi and Ge, 2022 ; Yuan et al, 2022 ). For example, a DOT1L peptide mimetic was synthesized to target DOT1L and AF9/ENL, and its use supressed growth of non-AMKL leukemic cell lines harboring KMT2A r ( Yuan et al, 2022 ). The most potent mimetic has similar anticancer activities to the DOT1L inhibitor EPZ5676 in KMT2 Ar non-AMKL cell lines, demonstrating that inhibition of interactions between DOT1L and a KMT2A fusion is a promising approach ( Yuan et al, 2022 ).…”

“…For example, a DOT1L peptide mimetic was synthesized to target DOT1L and AF9/ENL, and its use supressed growth of non-AMKL leukemic cell lines harboring KMT2A r ( Yuan et al, 2022 ). The most potent mimetic has similar anticancer activities to the DOT1L inhibitor EPZ5676 in KMT2 Ar non-AMKL cell lines, demonstrating that inhibition of interactions between DOT1L and a KMT2A fusion is a promising approach ( Yuan et al, 2022 ). DOT1L inhibitor EPZ5676 was trialled in pediatric and adult patients with KMT2A r refractory or relapsed leukemia (NCT02141828 and NCT01684150 clinical trials) ( Yi and Ge, 2022 ).…”

Discovery, Structure–Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein–Protein Interactions between AF9/ENL and AF4 or DOT1L

“…Two series of compounds have been reported to inhibit the AF9/ENL-DOT1L interactions, including our previously disclosed compound SYC-1456 [26] and a series of 7-mer peptidomimetic compounds derived from DOT1L, such as Cpd-10 [33,34] (Chart 1). These compounds can inhibit AF9-DOT1L and other related PPIs and selectively suppress aberrant gene expression and cell proliferation of MLL-r leukemia, showing on-target activities, as well as a need for additional inhibitor discovery and development.…”

Synthesis and biological evaluation of novel all-hydrocarbon cross-linked aza-stapled peptides

“…1 The larger surface areas of peptide structures have given superior target selectivity for interfering with PPIs compared to small molecule ligands, 2 spurring increased interest in applications to treat various diseases. 3 The need for chemical approaches for peptide modification has grown consequently to overcome the intrinsic protease susceptibility and limited bioavailability of peptides. 4 Cyclic peptides have exhibited increased protease stability, 5 improved target selectivity, 6 and better bioavailability 7 compared to their linear peptide counterparts.…”