Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells

Menendez-Gonzalez, Juan Bautista; Strange, Kathryn E.; Bassetto, Marcella; Brancale, Andrea; Rodrigues, Neil P.; Ferla, Salvatore

doi:10.3389/fddsv.2022.1013229

Cited by 3 publications

(1 citation statement)

References 25 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This can lead to unsatisfactory results, especially for highly flexible ligands. Thus, threedimensional ligand screening approaches can be more effective in identifying binders that can fit into the binding site and have been used for identifying novel binders successfully in the past [15][16][17][18][19][20]. However, ligand-based screening approaches neglect explicit knowledge of the receptor structure.…”

Section: Introductionmentioning

confidence: 99%

Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs

Kaiser,

Gertzen,

Bernauer

et al. 2023

Preprint

View full text Add to dashboard Cite

Desensitization of nicotinic acetylcholine receptors (nAChRs) can be induced by overstimulation with acetylcholine (ACh) caused by an insufficient degradation of ACh after poisoning with organophosphorus compounds (OPCs). Currently, there is no generally applicable treatment for OPC poisoning that directly targets the desensitized nAChR. The bispyridinium compound MB327, an allosteric modulator of nAChR, has been shown to act as a resensitizer of nAChRs, indicating that drugs binding directly to nAChRs can have beneficial effects after OPC poisoning. However, MB327 also acts as an inhibitor of nAChRs at higher concentrations and can thus not be used for OPC poisoning treatment. Consequently, novel, more potent resensitizers are required. To successfully design novel ligands, the knowledge of the binding site is of utmost importance. Recently, we performedin silicostudies to identify a new potential binding site of MB327, MB327-PAM-1, for which a more affine ligand, UNC0646, has been described. In this work, we performed ligand-based screening approaches to identify novel analogs of UNC0646 to help further understand the structure-affinity relationship of this compound class. Furthermore, we used structure-based screenings and identified compounds representing four new chemotypes binding to MB327-PAM-1. One of these compounds, cycloguanil, is the active metabolite of the antimalaria drug proguanil and shows a higher affinity towards MB327-PAM-1 than MB327. Furthermore, cycloguanil can reestablish the muscle force in soman-inhibited rat muscles. These results can act as a starting point to develop more potent resensitizers of nAChR and to close the gap in the treatment after OPC poisoning.

show abstract

Section: Introductionmentioning

confidence: 99%

Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs

Kaiser,

Gertzen,

Bernauer

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs

Kaiser,

Gertzen,

Bernauer

et al. 2024

Toxicology Letters

View full text Add to dashboard Cite

Impaired DNA damage response and inflammatory signalling underpins hematopoietic stem cell defects inGata2haploinsufficiency

Abdelfattah,

Habib,

Thomas

et al. 2024

Preprint

View full text Add to dashboard Cite

ClinicalGATA2deficiency syndromes arise from germline haploinsufficiency inducing mutations inGATA2, resulting in immunodeficiency that evolves to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). HowGATA2haploinsufficiency disrupts the function and transcriptional network of hematopoietic stem/progenitors (HSCs/HSPCs) to facilitate the shift from immunodeficiency to pre-leukemia is poorly characterised. Using a conditional mouse model harboring a single allele deletion ofGata2from the start of HSC developmentin utero, we identified pervasive defects in HSPC differentiation from young adultGata2haploinsufficient mice during B-cell development, early erythroid specification, megakaryocyte maturation to platelets and inflammatory cell generation.Gata2haploinsufficiency abolished HSC self-renewal and multi-lineage differentiation capacity. These functional alterations closely associated with deregulated DNA damage responses and inflammatory signalling conveyed fromGata2haploinsufficient HSCs. We identified genetic interplay betweenGata2andAsxl1, a driver of DNA damage and inflammation and, notably, a recurrent secondary mutation found inGATA2haploinsufficiency disease progression to MDS/AML. shRNA mediated knockdown ofAsxl1inGata2haploinsufficient HSPCs led to an enhanced differentiation blockin vitro. By analysis of HSCs from young adult compoundGata2/Asxl1haploinsufficient mice, we discovered hyperproliferation of double haploinsufficient HSCs, which were also functionally compromised in transplantation compared to their singleGata2 or Asxl1haploinsufficient counterparts. Through bothGata2/Asxl1dependent and unique transcriptional programs, HSCs from compoundGata2/Asxl1haploinsufficient fortified deregulated DNA damage responses and inflammatory signalling initiated inGata2haploinsufficient HSCs and established a broad pre-leukemic program. Our data reveal howGata2haploinsufficiency initially drives deregulation of HSC genome integrity and suggest the mechanisms of how secondary mutations likeASXL1take advantage of HSC genomic instability to nurture a pre-leukemic state inGATA2haploinsufficiency syndromes.

show abstract

Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells

Cited by 3 publications

References 25 publications

Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs

Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs

Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs

Impaired DNA damage response and inflammatory signalling underpins hematopoietic stem cell defects inGata2haploinsufficiency

Contact Info

Product

Resources

About