Discovery of Novel Benzothiazepinones as Irreversible Covalent Glycogen Synthase Kinase 3β Inhibitors for the Treatment of Acute Promyelocytic Leukemia

Abstract

Recently, irreversible inhibitors have attracted great interest in antitumors due to their advantages of forming covalent bonds to target proteins. Herein, some benzothiazepinone compounds (BTZs) have been designed and synthesized as novel covalent GSK-3β inhibitors with high selectivity for the kinase panel. The irreversible covalent binding mode was identified by kinetics and mass spectrometry, and the main labeled residue was confirmed to be the unique Cys14 that exists only in GSK-3β. The candidate 4-3 (IC 50 = 6.6 μM) showed good proliferation inhibition and apoptosis-inducing ability to leukemia cell lines, low cytotoxicity on normal cell lines, and no hERG inhibition, which hinted the potential efficacy and safety. Furthermore, 4-3 exhibited decent pharmacokinetic properties in vivo and remarkably inhibited tumor growth in the acute promyelocytic leukemia (APL) mouse model. All the results suggest that these newly irreversible BTZ compounds might be useful in the treatment of cancer such as APL.

Cyclization Reactions Involving 2-Aminoarenetellurols and Derivatives of α,β-Unsaturated Carboxylic Acids

“…e Te-C1 bond length of 2.1642(9) Å found for this compound is somewhat longer than 2.109(4) Å found for the equivalent bond of 2H-1,4benzotellurazin-3(4H)-one [27]. In the crystalline state, hydrogen bonding exists between the amide nitrogen and the carbonyl oxygen on adjacent molecules, but no supramolecular assembly mediated by secondary Te-N bonding is formed, in contrast to those observed for 1,3-tellurazoles [5,17].…”

“…iazepinone derivatives such as diltiazem have a long history as antidepressants [14] and as antihypertensives [15,16]. ey are currently under investigation for leukemia treatment [17]. Such characteristics may be enhanced in heavy chalcogen congeners due to their enhanced nucleophilicity [18], but there is a paucity of methods available for their preparation [19].…”

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

“…A reversible inhibitor targeting lysine residues has been disclosed very recently [ 201 ]. Regarding GSK-3, there are some examples of irreversible covalent inhibitors targeting cysteine residues [ 202 , 203 , 204 ]. Among these drugs, compound 4 - 3 seems particularly interesting, as it targets the unique Cys14 residue found in GSK-3β and inhibits cell growth in an acute promyelocytic leukemia murine model [ 204 ].…”

MIR-320a/b inhibits cell viability and cell cycle progression by targeting aryl hydrocarbon receptor nuclear translocator-like in acute promyelocyte leukaemia

“…During the pathological process of APL, leukaemia cells uncontrollably proliferate in the bone marrow and other haematopoietic tis-sues and then enter the peripheral blood to inhibit the proliferation of normal cells [4,5]. Multiple risk factors, such as viruses, genetic predisposition, chemical poisons, radiation, and drugs, can lead to APL [6]. Currently, therapies for APL include induced-differentiation therapy, arsenical therapy, and haematopoietic stem cell transplantation [7].…”