A Disulfonimide Catalyst for Highly Enantioselective Mukaiyama–Mannich Reaction

A new BINOL-derived chiral disulfonimide has been developed by introducing 4-methyl-3,5-dinitrophenyl substituents at its 3- and 3′-positions. This chiral disulfonimide catalyst displays high catalytic efficacy toward the asymmetric Mukaiyama–Mannich reaction of imines with ketene silyl acetals leading to β-amino acid esters in good yields (up to 99%) with high diastereoselectivities (<i>syn</i>/<i>anti</i> up to 97:3) and enantioselectivities (up to 98% ee). The long-standing problem of the chiral phosphoric acid-catalyzed asymmetric Mukaiyama–Mannich reaction that requires a 2-hydroxyphenyl moiety was solved by this disulfonimide catalyst

Copper-Catalyzed Desymmetric Intramolecular Ullmann C–N Coupling: An Enantioselective Preparation of Indolines

The first highly enantioselective copper-catalyzed intramolecular Ullmann C–N coupling reaction has been developed. The asymmetric desymmetrization of 1,3-bis­(2-iodoaryl)­propan-2-amines catalyzed by CuI/(R)-BINOL-derived ligands led to the enantioselective formation of indolines in high yields and excellent enantiomeric excesses. This method was also applied to the formation of 1,2,3,4-tetrahydroquinolines in high yields and excellent enantioselectivity

Copper-Catalyzed Desymmetric Intramolecular Ullmann C–N Coupling: An Enantioselective Preparation of Indolines

The first highly enantioselective copper-catalyzed intramolecular Ullmann C–N coupling reaction has been developed. The asymmetric desymmetrization of 1,3-bis­(2-iodoaryl)­propan-2-amines catalyzed by CuI/(R)-BINOL-derived ligands led to the enantioselective formation of indolines in high yields and excellent enantiomeric excesses. This method was also applied to the formation of 1,2,3,4-tetrahydroquinolines in high yields and excellent enantioselectivity

Synthesis of [1,2,3]Triazolo[1,5-<i>a</i>]quinoxalin-4(5<i>H</i>)-ones through Copper-Catalyzed Tandem Reactions of <i>N</i>-(2-Haloaryl)propiolamides with Sodium Azide

A simple and efficient approach for the synthesis of [1,2,3]triazolo[1,5-<i>a</i>]quinoxalin-4(5<i>H</i>)-ones is described. The methodology is based on a tandem reaction of 1-(2-haloaryl)propiolamides with sodium azide through a [3 + 2] azide–alkyne cycloaddition and intramolecular Ullmann-type C–N coupling process

Discovery of LLC0424 as a Potent and Selective <i>in Vivo</i> NSD2 PROTAC Degrader

Nuclear receptor-binding SET domain-containing 2 (NSD2), a methyltransferase that primarily installs the dimethyl mark on lysine 36 of histone 3 (H3K36me2), has been recognized as a promising therapeutic target against cancer. However, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none of them can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. Herein we report the discovery of a novel NSD2 degrader LLC0424 by leveraging the proteolysis-targeting chimera technology. LLC0424 potently degraded NSD2 protein with a DC50 value of 20 nM and a Dmax value of 96% in acute lymphoblastic leukemia (ALL) RPMI-8402 cells. Mechanistic studies revealed LLC0424 to selectively induce NSD2 degradation in a cereblon- and proteasome-dependent fashion. LLC0424 also caused continuous downregulation of H3K36me2 and growth inhibition of ALL cell lines with NSD2 mutation. Importantly, intravenous or intraperitoneal injection of LLC0424 showed potent NSD2 degradation in vivo

Discovery of LLC0424 as a Potent and Selective <i>in Vivo</i> NSD2 PROTAC Degrader

Nuclear receptor-binding SET domain-containing 2 (NSD2), a methyltransferase that primarily installs the dimethyl mark on lysine 36 of histone 3 (H3K36me2), has been recognized as a promising therapeutic target against cancer. However, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none of them can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. Herein we report the discovery of a novel NSD2 degrader LLC0424 by leveraging the proteolysis-targeting chimera technology. LLC0424 potently degraded NSD2 protein with a DC50 value of 20 nM and a Dmax value of 96% in acute lymphoblastic leukemia (ALL) RPMI-8402 cells. Mechanistic studies revealed LLC0424 to selectively induce NSD2 degradation in a cereblon- and proteasome-dependent fashion. LLC0424 also caused continuous downregulation of H3K36me2 and growth inhibition of ALL cell lines with NSD2 mutation. Importantly, intravenous or intraperitoneal injection of LLC0424 showed potent NSD2 degradation in vivo

Discovery of LLC0424 as a Potent and Selective <i>in Vivo</i> NSD2 PROTAC Degrader

Nuclear receptor-binding SET domain-containing 2 (NSD2), a methyltransferase that primarily installs the dimethyl mark on lysine 36 of histone 3 (H3K36me2), has been recognized as a promising therapeutic target against cancer. However, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none of them can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. Herein we report the discovery of a novel NSD2 degrader LLC0424 by leveraging the proteolysis-targeting chimera technology. LLC0424 potently degraded NSD2 protein with a DC50 value of 20 nM and a Dmax value of 96% in acute lymphoblastic leukemia (ALL) RPMI-8402 cells. Mechanistic studies revealed LLC0424 to selectively induce NSD2 degradation in a cereblon- and proteasome-dependent fashion. LLC0424 also caused continuous downregulation of H3K36me2 and growth inhibition of ALL cell lines with NSD2 mutation. Importantly, intravenous or intraperitoneal injection of LLC0424 showed potent NSD2 degradation in vivo