Condensation-Driven Assembly of Boron-Containing Bis(Heteroaryl) Motifs Using a Linchpin Approach

Herein, we describe the bromomethyl acyl boronate linchpin–an enabling reagent for the condensation-driven assembly of novel bis­(heteroaryl) motifs. This building block is readily accessible from commercially available starting materials. A variety of 2-amino- and 2-methylpyridines were reacted with MIDA-protected bromomethyl acylboronate to afford 2-boryl imidazo­[1,2-<i>a</i>]­pyridine and 2-boryl indolizine derivatives, respectively, in excellent yields. Subsequent condensation with hydroxyamidines and hydrazonamides converted the intermediate heterocycles into novel boron-containing bis­(heteroaryl) units characterized by high thermal stability

Condensation-Driven Assembly of Boron-Containing Bis(Heteroaryl) Motifs Using a Linchpin Approach

Herein, we describe the bromomethyl acyl boronate linchpin–an enabling reagent for the condensation-driven assembly of novel bis­(heteroaryl) motifs. This building block is readily accessible from commercially available starting materials. A variety of 2-amino- and 2-methylpyridines were reacted with MIDA-protected bromomethyl acylboronate to afford 2-boryl imidazo­[1,2-<i>a</i>]­pyridine and 2-boryl indolizine derivatives, respectively, in excellent yields. Subsequent condensation with hydroxyamidines and hydrazonamides converted the intermediate heterocycles into novel boron-containing bis­(heteroaryl) units characterized by high thermal stability

Condensation-Driven Assembly of Boron-Containing Bis(Heteroaryl) Motifs Using a Linchpin Approach

Herein, we describe the bromomethyl acyl boronate linchpin–an enabling reagent for the condensation-driven assembly of novel bis­(heteroaryl) motifs. This building block is readily accessible from commercially available starting materials. A variety of 2-amino- and 2-methylpyridines were reacted with MIDA-protected bromomethyl acylboronate to afford 2-boryl imidazo­[1,2-<i>a</i>]­pyridine and 2-boryl indolizine derivatives, respectively, in excellent yields. Subsequent condensation with hydroxyamidines and hydrazonamides converted the intermediate heterocycles into novel boron-containing bis­(heteroaryl) units characterized by high thermal stability

Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1)

WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure–activity relationship studies identified <i>N</i>-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein–protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-5 substituents. This allowed us to develop the first highly potent (<i>K</i>_disp < 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that <i>N</i>-(4-(4-methylpiperazin-1-yl)-3′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide <b>16d</b> (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5

Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1)

WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure–activity relationship studies identified <i>N</i>-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein–protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-5 substituents. This allowed us to develop the first highly potent (<i>K</i>_disp < 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that <i>N</i>-(4-(4-methylpiperazin-1-yl)-3′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide <b>16d</b> (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5