Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1

Abstract

Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.

In Silico Exploration of 1,7-Diazacarbazole Analogs as Checkpoint Kinase 1 Inhibitors by Using 3D QSAR, Molecular Docking Study, and Molecular Dynamics Simulations

“…The dataset used for molecular modeling studies contains 40 compounds which were designed and biological evaluation by Gazzard [14] to explore new 1, 7-diazacarbazole analogs as potent Chk1 inhibitors. The structures of the analogues as well as the pIC 50 values (pIC 50 = −logIC 50 ) are described in Table 1.…”

“…Surflex-Dock module implemented in Sybyl-X 2.0 was used for the molecular docking studies in this work. The crystal structures of ChK1 kinase domain were downloaded from the Protein Data Bank (PDB ID: 4RVK) [14]. The hydrogen atoms were added, as well as the water molecules, and the ligands had been deleted.…”

“…However, in vivo studies revealed that GNE-783 potently binds to acetylcholine esterase (AChE) and produces muscle fasciculation, thereby interrupting the development of this compound as a therapeutic agent. Gazzard et al [14] synthesized a novel series of GNE-783 analogs with oral availability to obtain superior bioactive compounds. The influence regularity of AChE bioactivity in AChE binding mode was described.…”

Multifunctional roles of leader protein of foot-and-mouth disease viruses in suppressing host antiviral responses

“…In addition to hijacking the host ubiquitination system for virus replication, many viruses have also developed the ability to disrupt cellular ubiquitination machinery to terminate or block several signaling transduction pathways responsible for the induction of antiviral responses [ 88 ]. So far, the PL pro of several coronaviruses such as, porcine epidemic diarrhea virus, SARS-CoV, and Middle East respiratory syndrome (MERS-CoV) have been shown to possess deubiquitination activity that antagonizes IFN production, indicating that PL pro is a multifunctional protein [ 89 , 90 ]. Similarly, FMDV L pro is a papain-like protease that acts as an antagonist of IFN by negatively regulating IFN transcription and IFN mRNA translation [ 8 , 18 , 42 , 77 ].…”

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

“…Its showed good metal chelation (Fe +2 , IC 50 = 18,660 nM) and metal reducing power for ferric (Fe +3 ) and cupric (Cu +2 ) ions. The 1,7-diazacarbazole analog 144 ( Figure 26) was a highly potent AChE inhibitor (IC 50 = 11 nM) in human and potent checkpoint kinase 1 (ChK1) inhibitor [220].…”